Acrylamide derivative, process for producing the same, and use

ABSTRACT

A compound represented by the formula:  
                 
 
wherein R 1  is a 5- or 6-membered ring; R 3  is a hydrogen atom, a lower alkyl group or a lower alkoxy group; R 7  and R 8  are each a hydrogen atom or a lower alkyl group; Z 1  is another 5- or 6-membered aromatic ring; Z 2  is a group represented by -Z 2a -W 1 -Z 2b - [wherein Z 2a  and Z 2b  are each O, S(O) m  (wherein m is 0, 1 or 2), an imino group or a bond, and W 1  is an alkylene chain]; X is CR (wherein R is a hydrogen atom, a lower alkyl group, a lower alkoxy group, an acyl group, or R and adjacent R 4  may form a 5- or 6-membered alicyclic heterocyclic group) or N; R 4  is NR 5 R 6  (wherein R 5  and R 6  are each a hydrogen atom, a hydrocarbon group, a heterocyclic group or an acyl group), or R 5  and R 6  are bonded to each other to form a heterocyclic group of NR 5 R 6 ; and R 2  is (1) an amino group which may be a quaternary ammonium or oxide, (2) a nitrogen-containing heterocyclic group which may contain a sulfur atom or an oxygen atom as the ring-constituting atom, in which the nitrogen atom may be converted to a quaternary ammonium or an oxide, or the like; 
or a salt thereof. The compound has excellent CCR5 antagonistic activity and thus is useful as a prophylactic and/or therapeutic medicine for HIV infection into human peripheral blood monocyte, especially for AIDS.

TECHNICAL FIELD

The present invention relates to a new cyclic compound having CCRantagonist activity, especially CCR5 antagonist activity, and to usethereof.

BACKGROUND ART

Recently, HIV (human immunodeficiency virus) protease inhibitors havebeen developed for treatment of AIDS (acquired immune deficiencysyndrome). With combined use of the protease inhibitors with two HIVreverse transcriptase inhibitors which have been commonly used,treatment of AIDS has made remarkable progress. However, the treatmentis still not efficient enough for the eradication of AIDS, anddevelopment of a new anti-AIDS medicine based on a different mechanismof action is desired.

As a receptor upon invasion of HIV into a target cell, CD4 has alreadybeen known. Recently, CCR5 as a second receptor of macrophage directedHIV, and CXCR4 as a second receptor of T cell directed HIV, which areG-protein coupled chemokine receptors having a seven-transmembraneprotein structure, have been found, and these chemokine receptors areconsidered to play an essential role for infection and transmission ofHIV. As a matter of fact, it has been reported that a man havingresistance to HIV infection even after repeated exposures to the virushad a mutation in which CCR5 gene was deleted homozygously. Thus, theCCR5 antagonists have been expected to become a new anti-HIV medicine,and examples of synthesis of new anilide derivatives having CCR5antagonist activity have been reported in the below-mentioned patentapplications such as Patent Document 1, Patent Document 2 and PatentDocument 3, while there has been no report of a CCR5 antagonist whichhas been commercialized as a therapeutic medicine for AIDS. Further, acompound having CCR5 antagonist activity is described to be useful as aprophylactic and/or therapeutic medicine for AIDS in the below-mentionedPatent Document 4, but said compound has a different structure from thecompound of the present invention.

Patent Document 1: WO99/32100

Patent Document 2: Japanese Patent Application No. 10-234388

Patent Document 3: Japanese Patent Application No. 10-363404

Patent Document 4: JP-A No. 2001-026586

DISCLOSURE OF THE INVENTION

The present invention is to provide a new bicyclic compound that isuseful for preventing and treating HIV infection, especially AIDS, dueto its CCR antagonist activity, especially CCR5 antagonist activity.

The present inventors have intensively studied compounds having CCR5antagonist activity and found that a compound of the following formula(I) or a salt thereof (hereinafter, sometimes referred to as Compound(I)) has a clinically favorable pharmacological effect including CCRantagonist activity, especially excellent CCR5 antagonist activity,thereby completing the invention.

Thus, the invention provides:

[1] a compound represented by the formula:

wherein R¹ is a 5- or 6-membered ring which may be substituted;

R³ is a hydrogen atom, a lower alkyl group which may be substituted or alower alkoxy group which may be substituted;

R⁷ and R⁸ are each a hydrogen atom or a lower alkyl group which may besubstituted;

Z¹ is a 5- or 6-membered aromatic ring which may be further substituted;

Z is a group represented by -Z^(2a)-W¹-Z^(2b)-, wherein Z^(2a) andZ^(2b) are each O, S(O)_(m) (wherein m is 0, 1 or 2), an imino groupwhich may be substituted, or a bond, and W¹ is an alkylene chain whichmay be substituted, an alkenylene chain which may be substituted, or abond;

X is N or CR, wherein R represents a hydrogen atom, a lower alkyl groupwhich may be substituted, a lower alkoxy group which may be substitutedor an acyl group which may be substituted, or R and the adjacent R⁴ mayform a 5- or 6-membered alicyclic heterocyclic group;

R⁴ is NR⁵R⁶, wherein R⁵ and R⁶ each represent a hydrogen atom, ahydrocarbon group which may be substituted, a heterocyclic group whichmay be substituted or an acyl group which may be substituted, or R⁵ andR⁶ are bonded to each other to form a heterocyclic group which may besubstituted represented by NR⁵R⁶; and

R² is (1) an amino group which may be substituted, in which the nitrogenatom may be converted to a quaternary ammonium or an oxide, (2) anitrogen-containing heterocyclic group which may be substituted and maycontain a sulfur atom or an oxygen atom as the ring-constituting atom,in which the nitrogen atom may be converted to a quaternary ammonium oran oxide, (3) a group represented by the formula:

wherein k represents 0 or 1, and when k is 0, the phosphorus atom mayform a phosphonium salt; R⁹ and R¹⁰ are each a hydrocarbon group whichmay be substituted, a hydroxy group which may be substituted or an aminogroup which may be substituted; or R⁹ and R¹⁰ may be bonded to eachother to form a cyclic group with the adjacent phosphorus atom, (4) anamidino group which may be substituted, or (5) a guanidino group whichmay be substituted; or a salt thereof;

[2] a prodrug of the compound according to the above [1];

[3] the compound according to the above [1], wherein R¹ is a benzene, afuran, a thiophene, a pyridine, a cyclopentane, a cyclohexane, apyrrolidine, a piperidine, a piperazine, a morpholine, a thiomorpholineor a tetrahydropyran, each of which may be substituted;

[4] the compound according to the above [1], wherein R¹ is a benzenewhich may be substituted;

[5] the compound according to the above [1], wherein NR⁵R⁶ is aheterocyclic group which may be substituted;

[6] the compound according to the above [1], wherein Z¹ is a benzenewhich may be substituted with a substituent selected from (1) a halogenatom, (2) a C₁₋₄ alkyl group which may be substituted with halogenatom(s), and (3) a C₁₋₄ alkoxy group which may be substituted with ahalogen atom;

[7] the compound according to the above [1], wherein Z¹ is a benzenewhich may be substituted with a methyl group or a trifluoromethyl group;

[8] the compound according to the above [1], wherein Z² is a grouprepresented by -Z^(2a)-W²-Z^(2b), wherein Z^(2a) and Z^(2b) are each O,S(O)_(m) (wherein m is 0, 1 or 2), an imino group which may besubstituted, or a bond, and W² is an alkylene chain which may besubstituted;

[9] the compound according to the above [1], wherein Z² is a grouprepresented by —CH₂—, —CH(OH)— or —S(O)_(m)—CH₂— (wherein m is 0, 1 or2);

[10] the compound according to the above [1], wherein Z² is a grouprepresented by —S(O)_(n)—CH₂— (wherein m is 0, 1 or 2);

[11] the compound according to the above [1], wherein R² is (1) an aminogroup which may be substituted, in which the nitrogen atom may beconverted to a quaternary ammonium or an oxide, (2) anitrogen-containing heterocyclic group which may be substituted and maycontain a sulfur atom or an oxygen atom as the ring-constituting atom,in which the nitrogen atom may be converted to a quaternary ammonium oran oxide, (3) an amidino group which may be substituted, or (4) aguanidino group which may be substituted;

[12] the compound according to the above [1], wherein R² is an aminogroup which may be substituted, or a nitrogen-containing heterocyclicgroup which may be substituted and may contain a sulfur atom or anoxygen atom as the ring-constituting atom;

[13] the compound according to the above [1], wherein R² is —NRR′,wherein R and R′ are each an aliphatic hydrocarbon group which may besubstituted or an alicyclic heterocyclic group which may be substituted;

[14] the compound according to the above [1], wherein R² is anitrogen-containing aromatic heterocyclic group which may besubstituted;

[15] the compound according to the above [1], wherein R² is animidazolyl group which may be substituted or a triazolyl group which maybe substituted;

[16] the compound according to the above [1], wherein R¹ is a benzene, afuran, a thiophene, a pyridine, a cyclopentane, a cyclohexane, apyrrolidine, a piperidine, a piperazine, a morpholine, a thiomorpholineor a tetrahydropyran, each of which may be substituted with a halogen, anitro, a cyano, a C₁₋₆ alkyl, a C₁₋₆ alkoxy, a C₁₋₆ an alkoxy-C₁₋₆ alkylor a C₁₋₆ alkoxy-C₁₋₆ alkoxy;

Z¹ is benzene which may be substituted with a substituent selected from(1) a halogen atom, (2) a C₁₋₄ alkyl group which may be substituted witha halogen atom, and (3) a C₁₋₄ alkoxy group which may be substitutedwith a halogen atom;

Z² is -Z^(2a)-W¹-Z^(2b)-, wherein Z^(2a) and Z^(2b) are each O, S(O)_(m)(wherein m is 0, 1 or 2), an imino group which may be substituted with aC₁₋₄ alkyl group, or a bond, and W¹ is a bond, or a C₁₋₄ alkylene chainor a C₂₋₄ alkenylene chain, each of which may be substituted with a C₁₋₆alkyl, a hydroxy group, a hydroxyimino or a C₁₋₆ alkoxyimino; and

R² is an amino group which may be substituted with a C₁₋₄ alkyl group,or a nitrogen-containing heterocyclic group which may contain a sulfuratom or an oxygen atom as the ring-constituting atom and may besubstituted with a C₁₋₄ alkyl group;

[17] a compound represented by the formula:

wherein R^(1a) is a (C₁₋₆ alkoxy-C₁₋₆ alkoxy)phenyl;

R^(2a) is (1) an N-C₁₋₆ alkyl-N-tetrahydropyranylamino, (2) animidazolyl which may be substituted with a C₁₋₆ alkyl which may besubstituted, or (3) a triazolyl which may be substituted with a C₁₋₆alkyl which may be substituted;

R^(4a) is NR^(5a)R^(6a) wherein R^(5a) and R^(6a) are bonded to eachother to form a heterocyclic group which may be substituted representedby NR^(5a)R^(6a);

X^(a) is CH or N;

na is 0 or 1;

Z^(2a) is a bond, S, SO or SO₂; and

the other symbols have the same meanings as defined above; or a saltthereof;

[18] the compound according to the above [17], wherein Z^(2a) is SO;

[19] the compound according to the above [18], wherein Z^(2a) is SOhaving a configuration of (S);

[20] the compound according to the above [17], wherein R^(4a) is a1-pyrrolidinyl group which may be substituted;

[21](Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide,(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-[3-(hydroxymethyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide,(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-carboxypyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol)-5-yl]methyl]sulfinyl]phenyl]acrylamideand diastereomers thereof;

[22](Ss)-(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-[3-(hydroxymethyl)pyrrolidin-1-yl]pyridin-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamideand a diastereomer thereof, and(S)-(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-pyrrolidin-1-ylpyridin-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidzol-5-yl)methyl]sulfinyl]phenyl]acrylamide;

[23] a process for producing a compound represented by the formula:

wherein R^(2″) is (1) an amino group which may be substituted, in whichthe nitrogen atom may be converted to a quaternary ammonium, (2) anitrogen-containing heterocyclic group which may be substituted and maycontain a sulfur atom or an oxygen atom as the ring-constituting atom,in which the nitrogen atom may be converted to a quaternary ammonium, or(3) a group represented by formula (Ia), and the other symbols have thesame meanings as defined above, or a salt thereof, which comprisessubjecting a compound represented by the formula:

wherein each symbol has the same meaning as defined above, a salt or areactive derivative thereof, and a compound represented by the formula:

wherein each symbol has the same meaning as defined above, or a saltthereof to a condensation reaction, and then optionally to deprotection,oxidation-reduction and/or quaternization reaction;

[24] a pharmaceutical composition comprising the compound represented byformula (I), a salt or prodrug thereof;

[25] the pharmaceutical composition according to the above [24], whichis a CCR antagonist;

[26] the pharmaceutical composition according to the above [25], whereinCCR is CCR5 and/or CCR2;

[27] the pharmaceutical composition according to the above [25], whereinCCR is CCR5;

[28] the pharmaceutical composition according to the above [24], whichis a prophylactic and/or therapeutic agent for HIV infection, chronicrheumatoid arthritis, autoimmune diseases, allergic diseases, ischemicbrain cell disorder, cardiac infarction, nephritis/nephropathy orarteriosclerosis;

[29] the pharmaceutical composition according to the above [24], whichis a prophylactic and/or therapeutic agent for HIV infection;

[30] the pharmaceutical composition according to the above [24], whichis a prophylactic and/or therapeutic agent for AIDS;

[31] the pharmaceutical composition according to the above [24], whichis a suppressive agent for disease progression of AIDS;

[32] a method for preventing or treating HIV infection, chronicrheumatoid arthritis, autoimmune diseases, allergic diseases, ischemicbrain cell disorder, cardiac infarction, nephritis/nephropathy,arteriosclerosis or graft-versus-host diseases, which comprisesadministering an effective amount of the compound according to the above[1], a salt or prodrug thereof to a subject in need thereof; and

[33] use of the compound according to the above [1], a salt or prodrugthereof, for the manufacture of a prophylactic and/or therapeutic agentfor HIV infection, chronic rheumatoid arthritis, autoimmune diseases,allergic diseases, ischemic brain cell disorder, cardiac infarction,nephritis/nephropathy, arteriosclerosis or graft-versus-host diseases.

BEST MODE FOR CARRYING OUT THE INVENTION

In the above-described formula (I), the “5- or 6-membered ring” in the“5- or 6-membered ring group which may be substituted” represented by R¹may be exemplified by a group which is formed by eliminating a hydrogenatom from 6-membered aromatic hydrocarbon such as benzene, etc.; 5- or6-membered aliphatic hydrocarbon such as cyclopentane, cyclohexane,cyclopentene, cyclohexene, cyclopentanediene, cyclohexanediene, etc.; 5-or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms of oneor two kinds selected from nitrogen, sulfur and oxygen atoms, such asfuran, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole,isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine,pyridazine, triazole, etc.; 5- or 6-membered non-aromatic heterocyclecontaining 1 to 4 heteroatoms of one or two kinds selected fromnitrogen, sulfur and oxygen atoms, such as tetrahydrofuran,tetrahydrothiophene, dithiolane, oxathiolane, pyrrolidine, pyrroline,imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine,piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine,thiomorpholine, pyran, tetrahydropyran, tetrahydrothiopyran, etc.; orthe like. Among them, the “5- or 6-membered ring” is preferably benzene,furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine,piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran(preferably, 6-membered ring), or the like, it being particularlypreferably benzene.

The substituent which may be carried by the “5- or 6-membered ring” ofthe “5- or 6-membered ring group which may be substituted” representedby R¹ may be exemplified by halogen atom, nitro, cyano, alkyl which maybe substituted, cycloalkyl which may be substituted, hydroxy group whichmay be substituted, thiol group which may be substituted (wherein thesulfur atom may be oxidized, and may form sulfinyl which may besubstituted or sulfonyl which may be substituted), amino group which maybe substituted, acyl which may be substituted, carboxyl group which maybe esterified, an aromatic group which may be substituted, or the like.

Examples of the halogen as the substituent of R¹ include fluorine,chlorine, bromine, iodine and the like, it being preferably fluorine andchlorine.

The alkyl of the “alkyl which may be substituted” as the substituent ofR¹ may be exemplified by linear or branched alkyl having 1 to 10 carbonatoms, for example, C₁₋₁₀ alkyl such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., and preferablylower (C₁₋₆) alkyl. Examples of the substituent of the “alkyl which maybe substituted” include halogen (for example, fluorine, chlorine,bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group whichmay be substituted (for example, thiol group, C₁₋₄ alkylthio, etc.),amino group which may be substituted (for example, amino, mono-C₁₋₄alkylamino, di-C₁₋₄ alkylamino, 5- or 6-membered cycloamino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc.), carboxyl group which may be esterified oramidated (for example, carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl,mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.), C₁₋₄ alkoxywhich may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy, etc.), C₁₋₄ alkoxy-C₁₋₄ alkoxy whichmay be halogenated (for example, methoxymethoxy, methoxyethoxy,ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.),formyl, C₂₋₄ alkanoyl (for example, acetyl, propionyl, etc.), C₁₋₄alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl, etc.), andthe like, and the number of the substituents is preferably 1 to 3.

Examples of the cycloalkyl of the “cycloalkyl which may be substituted”as the substituent of R¹ include C₃₋₇ cycloalkyl such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Examples of thesubstituent in the “cycloalkyl which may be substituted” include halogen(for example, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano,hydroxy group, thiol group which may be substituted (for example, thiol,C₁₋₄ alkylthio, etc.), amino group which may be substituted (forexample, amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- or6-membered cycloamino such as tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, etc.), carboxyl groupwhich may be esterified or amidated (for example, carboxyl, C₁₋₄alkoxycarbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, etc.), C₁₋₄ alkoxy which may be halogenated (forexample, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,trifluoroethoxy, etc.), C₁₋₄ alkoxy-C₁₋₄ alkoxy which may be halogenated(for example, methoxymethoxy, methoxyethoxy, ethoxyethoxy,trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C₂₋₄alkanoyl (for example, acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (forexample, methanesulfonyl, ethanesulfonyl, etc.), and the like, and thenumber of the substituents is preferably 1 to 3.

The substituent of the “hydroxy group which may be substituted” as thesubstituent of R¹ may be exemplified by (1) alkyl which may besubstituted (for example, C₁₋₁₀ alkyl such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., and preferablylower (C₁₋₆) alkyl; or the like);

(2) cycloalkyl which may be substituted and may contain heteroatom(s)(for example, C₃₋₇ cycloalkyl such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, etc.; 5- or 6-membered saturatedheterocyclic group containing 1 or 2 heteroatoms, such astetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,tetrahydropyranyl, tetrahydrothiopyranyl, etc., and preferablytetrahydropyranyl, etc.; or the like);

(3) alkenyl which may be substituted (for example, alkenyl having 2 to10 carbon atoms, such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., andpreferably lower (C₂₋₆) alkenyl; or the like);

(4) cycloalkenyl which may be substituted (for example, cycloalkenylhaving 3 to 7 carbon atoms, such as 2-cyclopentenyl, 2-cyclohexenyl,2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.; or the like);

(5) aralkyl which may be substituted (for example, phenyl-C₁₋₄ alkylsuch as benzyl, phenethyl, etc.; or the like);

(6) formyl, or acyl which may be substituted (for example, alkanoylhaving 2 to 4 carbon atoms, such as acetyl, propionyl, butyryl,isobutyryl, etc.), alkylsulfonyl having 1 to 4 carbon atoms (forexample, methanesulfonyl, ethanesulfonyl, etc.), or the like);

(7) aryl which may be substituted (for example, phenyl, naphthyl, etc.);or the like.

The substituent of the above-described (1) alkyl which may besubstituted, (2) cycloalkyl which may be substituted, (3) alkenyl whichmay be substituted, (4) cycloalkenyl which may be substituted, (5)aralkyl which may be substituted, (6) acyl which may be substituted, and(7) aryl which may be substituted, may be exemplified by halogen (forexample, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano,hydroxy group, thiol group which may be substituted (for example, thiol,C₁₋₄ alkylthio, etc.), amino group which may be substituted (forexample, amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- or6-membered cycloamino such as tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, etc.), carboxyl groupwhich may be esterified or amidated (for example, carboxyl, C₁₋₄alkoxycarbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, etc.), C₁₋₄ alkyl which may be halogenated (for example,trifluoromethyl, methyl, ethyl, etc.), C₁₋₆ alkoxy which may behalogenated (for example, methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy, etc.; preferably C₁₋₄ alkoxy whichmay be halogenated), formyl, C₂₋₄ alkanoyl (for example, acetyl,propionyl, etc.), C₁₋₄ alkylsulfonyl (for example, methanesulfonyl,ethanesulfonyl, etc.), 5- or 6-membered aromatic heterocycle which maybe substituted [for example, 5- or 6-membered aromatic heterocyclecontaining 1 to 4 heteroatoms of one or two kinds selected fromnitrogen, sulfur and oxygen atoms, such as furan, thiophene, pyrrole,imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole,tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, etc.;examples of the substituent which may be carried by said heterocycleinclude halogen (for example, fluorine, chlorine, bromine, iodine,etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxylgroup, C₁₋₄ alkyl which may be halogenated (for example,trifluoromethyl, methyl, ethyl, etc.), C₁₋₄ alkoxy which may behalogenated (for example, methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy, etc.), formyl, C₂₋₄ alkanoyl (forexample, acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (for example,methanesulfonyl, ethanesulfonyl, etc.), and the like; and the number ofthe substituents is preferably 1 to 3], or the like; and the number ofthe substituents is preferably 1 to 3.

The substituent of the “thiol group which may be substituted” as thesubstituent of R¹ may be exemplified by the same one as the “substituentof hydroxy group which may be substituted as the substituent of R¹,” andpreferred among them are:

(1) alkyl which may be substituted (for example, C₁₋₁₀ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., and preferably lower (C₁₋₆) alkyl; or the like);

(2) cycloalkyl which may be substituted (for example, C₃₋₇ cycloalkylsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,etc., or the like);

(3) aralkyl which may be substituted (for example, phenyl-C₁₋₄ alkylsuch as benzyl, phenethyl, etc.);

(4) aryl which may be substituted (for example, phenyl, naphthyl, etc.);and the like.

The substituent which may be carried by the above-described (1) alkylwhich may be substituted, (2) cycloalkyl which may be substituted, (3)aralkyl which may be substituted, and (4) aryl which may be substituted,may be exemplified by halogen (for example, fluorine, chlorine, bromine,iodine, etc.), nitro, cyano, hydroxy group, thiol group which may besubstituted (for example, thiol, C₁₋₄ alkylthio, etc.), amino groupwhich may be substituted (for example, amino, mono-C₁₋₄ alkylamino,di-C₁₋₄ alkylamino, 5- or 6-membered cycloamino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc.), carboxyl group which may be esterified oramidated (for example, carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl,mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.), C₁₋₄ alkoxywhich may be halogenated (for example, methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy, etc.), C₁₋₄ alkoxy-C₁₋₄ alkoxy whichmay be halogenated (for example, methoxymethoxy, methoxyethoxy,ethoxyethoxy, trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.),formyl, C₂₋₄ alkanoyl (for example, acetyl, propionyl, etc.), C₁₋₄alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl, etc.), orthe like, and the number of the substituents is preferably 1 to 3.

The substituent of the “amino group which may be substituted” as thesubstituent of R¹ may be exemplified by the same one as the “substituentof hydroxy group which may be substituted as the substituent of R¹,” andthe number of substituents on the amino group may be 1 or 2. Among them,the substituent is preferably:

(1) alkyl which may be substituted (for example, C₁₋₁₀ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., and preferably lower (C₁₋₁₀) alkyl, or the like);

(2) cycloalkyl which may be substituted (for example, C₃₋₇ cycloalkylgroup such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, etc., or the like);

(3) alkenyl which may be substituted (for example, alkenyl having 2 to10 carbon atoms, such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., andpreferably lower (C₂₋₆) alkenyl, or the like);

(4) cycloalkenyl which may be substituted (for example, cycloalkenylhaving 3 to 7 carbon atoms, such as 2-cyclopentenyl, 2-cyclohexenyl,2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.; or the like);

(5) formyl, or acyl which may be substituted (for example, alkanoylhaving 2 to 4 carbon atoms (for example, acetyl, propionyl, butyryl,isobutyryl, etc.), alkylsulfonyl having 1 to 4 carbon atoms (forexample, methanesulfonyl, ethanesulfonyl, etc.) or the like);

(6) aryl which may be substituted (for example, phenyl, naphthyl, etc.);and the like.

Examples of the substituent of the above-described (1) alkyl which maybe substituted, (2) cycloalkyl which may be substituted, (3) alkenylwhich may be substituted, (4) cycloalkenyl which may be substituted, (5)acyl which may be substituted, (6) aryl which may be substituted,include halogen (for example, fluorine, chlorine, bromine, iodine,etc.), nitro, cyano, hydroxy group, thiol group which may be substituted(for example, thiol, C₁₋₄ alkylthio, etc.), amino group which may besubstituted (for example, amino, mono-C₁₋₄ alkylamino, di-C₁₋₄alkylamino, 5- or 6-membered cycloamino such as tetrahydropyrrole,piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole,etc.), carboxyl group which may be esterified or amidated (for example,carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl,di-C₁₋₄ alkylcarbamoyl, etc.), C₁₋₄ alkoxy which may be halogenated (forexample, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,trifluoroethoxy, etc.), C₁₋₄ alkoxy-C₁₋₄ alkoxy which may be halogenated(for example, methoxymethoxy, methoxyethoxy, ethoxyethoxy,trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C₂₋₄alkanoyl (for example, acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (forexample, methanesulfonyl, ethanesulfonyl, etc.), and the like, and thenumber of the substituents is preferably 1 to 3.

Further, the substituents of the “amino group which may be substituted”as the substituent of R¹ may be bonded to each other to form acycloamino group (for example, a group which is formed by eliminating ahydrogen atom from the ring-constituting nitrogen atom of a 5- or6-membered ring such as tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, etc. so that a bond ismade available on the nitrogen atom, or the like). This cycloamino groupmay be substituted, and examples of the substituent include halogen (forexample, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano,hydroxy group, thiol group which may be substituted (for example, thiol,C₁₋₄ alkylthio, etc.), amino group which may be substituted (forexample, amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- or6-membered cycloamino such as tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, etc.), carboxyl groupwhich may be esterified or amidated (for example, carboxyl, C₁₋₄alkoxycarbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, etc.), C₁₋₄ alkoxy which may be halogenated (forexample, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,trifluoroethoxy, etc.), C₁₋₄ alkoxy-C₁₋₄ alkoxy which may halogenated(for example, methoxymethoxy, methoxyethoxy, ethoxyethoxy,trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C₂₋₄alkanoyl (for example, acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (forexample, methanesulfonyl, ethanesulfonyl, etc.), and the like, while thenumber of the substituents is preferably 1 to 3.

The “acyl which may be substituted” as the substituent of R¹ may beexemplified by a group in which

(1) hydrogen;

(2) alkyl which may be substituted (for example, C₁₋₁₀ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., and preferably lower (C₁₋₆) alkyl, or the like);

(3) cycloalkyl which may be substituted (for example, C₃₋₇ cycloalkylsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,etc., or the like);

(4) alkenyl which may be substituted (for example, alkenyl having 2 to10 carbon atoms, such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., andpreferably lower (C₂₋₆) alkenyl, or the like);

(5) cycloalkenyl which may be substituted (for example, cycloalkenyl of3 to 7 carbon atoms, such as 2-cyclopentenyl, 2-cyclohexenyl,2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc., or the like);

(6) 5- or 6-membered monocyclic aromatic group which may be substituted(for example, phenyl, pyridyl, etc.) or the like; is bonded to acarbonyl group or a sulfonyl group (for example, formyl, acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl,heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl,cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl,2-cyclohexenecarbonyl, benzoyl, nicotinoyl, methanesulfonyl,ethanesulfonyl, etc.). Examples of the substituent of theabove-described (2) alkyl which may be substituted, (3) cycloalkyl whichmay be substituted, (4) alkenyl which may be substituted, (5)cycloalkenyl which may be substituted, and (6) 5- or 6-memberedmonocyclic aromatic group which may be substituted, include halogen (forexample, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano,hydroxy group, thiol group which may be substituted (for example, thiol,C₁₋₄ alkylthio, etc.), amino group which may be substituted (forexample, amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- or6-membered cycloamino such as tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, etc.), carboxyl groupwhich may be esterified or amidated (for example, carboxyl, C₁₋₄alkoxycarbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, etc.), C₁₋₄ alkoxy which may be halogenated (forexample, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,trifluoroethoxy, etc.), C₁₋₄ alkoxy-C₁₋₄ alkoxy which may be halogenated(for example, methoxymethoxy, methoxyethoxy, ethoxyethoxy,trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C₂₋₄alkanoyl (for example, acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (forexample, methanesulfonyl, ethanesulfonyl, etc.), and the like, and thenumber of the substituents is preferably 1 to 3.

The “carboxyl which may be esterified” as the substituent of R¹ may beexemplified by a group in which (1) hydrogen;

(2) alkyl which may be substituted (for example, C₁₋₁₀ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., and preferably lower (C₁₋₆) alkyl, or the like);

(3) cycloalkyl which may be substituted (for example, C₃₋₇ cycloalkylsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,etc., or the like);

(4) alkenyl which may be substituted (for example, alkenyl having 2 to10 carbon atoms, such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., andpreferably lower (C₂₋₆) alkenyl, or the like);

(5) cycloalkenyl which may be substituted (for example, cycloalkenylhaving 3 to 7 carbon atoms, such as 2-cyclopentenyl, 2-cyclohexenyl,2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);

(6) aryl which may be substituted (for example, phenyl, naphthyl, etc.);or the like is bonded to a carbonyloxy group, preferably carboxyl, lower(C₁₋₆) alkoxycarbonyl, aryloxycarbonyl (for example, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, naphthoxycarbonyl,etc.), or the like.

Examples of the substituent of the above-described (2) alkyl which maybe substituted, (3) cycloalkyl which may be substituted, (4) alkenylwhich may be substituted, (5) cycloalkenyl which may be substituted, and(6) aryl which may be substituted, include halogen (for example,fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group,thiol group which may be substituted (for example, thiol, C₁₋₄alkylthio, etc.), amino group which may be substituted (for example,amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- or 6-memberedcycloamino such as tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, etc.), carboxyl groupwhich may be esterified or amidated (for example, carboxyl, C₁₋₄alkoxycarbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, etc.), C₁₋₄ alkoxy which may be halogenated (forexample, methoxy, ethoxy, propoxy, butoxy, trifluoromethoxy,trifluoroethoxy, etc.), C₁₋₄ alkoxy-C₁₋₄ alkoxy which may halogenated(for example, methoxymethoxy, methoxyethoxy, ethoxyethoxy,trifluoromethoxyethoxy, trifluoroethoxyethoxy, etc.), formyl, C₂₋₄alkanoyl (for example, acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (forexample, methanesulfonyl, ethanesulfonyl, etc.), and the like, and thenumber of the substituents is preferably 1 to 3.

The “aromatic group” of the “aromatic group which may be substituted” asthe substituent of R¹ may be exemplified by 5- or 6-membered homocyclicor heterocyclic aromatic group such as phenyl, pyridyl, furyl, thienyl,pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl,isoxazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl,etc.; fused heterocyclic aromatic group such as benzofuran, indole,benzothiophene, benzoxazole, benzothiazole, indazole, benzimidazole,quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline,cinnoline, imidazopyridine, etc.; or the like. Examples of thesubstituent of the aromatic group include halogen (for example,fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group,thiol group which may be substituted (for example, thiol, C₁₋₄alkylthio, etc.), amino group which may be substituted (for example,amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- or 6-memberedcycloamino such as tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, etc.), carboxyl groupwhich may be esterified or amidated (for example, carboxyl, C₁₋₄alkoxycarbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, etc.), C₁₋₄ alkyl which may be halogenated (for example,trifluoromethyl, methyl, ethyl, etc.), C₁₋₄ alkoxy which may behalogenated (for example, methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy, etc.), formyl, C₂₋₄ alkanoyl (forexample, acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (for example,methanesulfonyl, ethanesulfonyl, etc.), and the like, and the number ofthe substituents is preferably 1 to 3.

The number of the above substituents of R¹ may be 1 to 4, preferably 1to 2, and the substituents which may be identical with or different fromeach other may be present at any possible positions of the ring. Whenthe “5- or 6-membered ring” of the “5- to 6-membered ring which may besubstituted” represented by R¹ has two or more substituents, two of thesubstituents may be bonded to each other to form, for example, lower(C₁₋₆) alkylene (for example, trimethylene, tetramethylene, etc.), lower(C₁₋₆) alkyleneoxy (for example, —CH₂—O—CH₂—, —O—CH₂—CH₂—,—O—CH₂—CH₂—CH₂—, —O—CH₂—CH₂—CH₂—CH₂—, —O—C(CH₃) (CH₃)—CH₂—CH₂—, etc.),lower (C₁₋₆) alkylenethio (for example, —CH₂—S—CH₂—, —S—CH₂—CH₂—,—S—CH₂—CH₂—CH₂—, —S—CH₂—CH₂—CH₂—CH₂—, —S—C(CH₃) (CH₃)—CH₂—CH₂—, etc.),lower (C₁₋₆) alkylenedioxy (for example, —O—CH₂—O—, —O—CH₂—CH₂—O—,—O—CH₂—CH₂—CH₂—O—, etc.), lower (C₁₋₆) alkylenedithio (for example,—S—CH₂—S—, —S—CH₂—CH₂—S—, —S—CH₂—CH₂—CH₂—S—, etc.), oxy-lower (C₁₋₆)alkyleneamino (for example, —O—CH₂—NH—, —O—CH₂—CH₂—NH—, etc.), oxy-lower(C₁₋₆) alkylenethio (for example, —O—CH₂—S—, —O—CH₂—CH₂—S—, etc.), lower(C₁₋₆) alkyleneamino (for example, —NH—CH₂—CH₂—, —NH—CH₂—CH₂—CH₂—,etc.), lower (C₁₋₆) alkylenediamino (for example, —NH—CH₂—NH—,—NH—CH₂—CH₂—NH—, etc.), thialower (C₁₋₆) alkyleneamino (for example,—S—CH₂—NH—, —S—CH₂—CH₂—NH—, etc.), lower (C₂₋₆) alkenylene (for example,—CH₂—CH═CH—, —CH₂—CH₂—CH═CH—, —CH₂—CH═CH—CH₂—, etc.) lower (C₄₋₆)alkadienylene (for example, —CH═CH—CH═CH—, etc.), and the like.

Further, the divalent group formed by bonding of two substituents of R¹may contain 1 to 3 substituents which are the same as the “substituents”of the “5- or 6-membered ring” of the “5- or 6-membered ring which maybe substituted” represented by R¹ (halogen atom, nitro, cyano, alkylwhich may be substituted, cycloalkyl which may be substituted, hydroxygroup which may be substituted, thiol group which may be substituted(wherein the sulfur atom may be oxidized, and may form sulfinyl groupwhich may be substituted or sulfonyl group which may be substituted),amino group which may be substituted, acyl which may be substituted,carboxyl group which may be esterified or amidated, an aromatic groupwhich may be substituted, and the like).

The “substituent” of the “5- or 6-membered ring” of the “5- or6-membered ring group which may be substituted” represented by R¹ may beexemplified by, in particular, lower (C₁₋₄) alkyl which may behalogenated or lower (C₁₋₄) alkoxylated (for example, methyl, ethyl,t-butyl, trifluoromethyl, methoxymethyl, ethoxymethyl, propoxymethyl,butoxymethyl, methoxyethyl, ethoxylethyl, propoxyethyl, butoxyethyl,etc.), lower (C₁₋₄) alkoxy which may be halogenated or lower (C₁₋₄)alkoxylated (for example, methoxy, ethoxy, propoxy, butoxy, t-butoxy,trifluoromethoxy, methoxymethoxy, ethoxymethoxy, propoxymethoxy,butoxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, butoxyethoxy,methoxypropoxy, ethoxypropoxy, propoxypropoxy, butoxypropoxy, etc.),halogen (for example, fluorine, chlorine, etc.), nitro, cyano, aminowhich may be substituted with one or two of lower (C₁₋₄) alkyl, formylor lower (C₂₋₄) alkanoyl (for example, amino, methylamino,dimethylamino, formylamino, acetylamino, etc.), 5- or 6-memberedcycloamino (for example, 1-pyrrolidinyl, 1-piperazinyl, 1-piperidinyl,4-morpholino, 4-thiomorpholino, 1-imidazolyl, 4-tetrahydropyranyl,etc.), or the like.

Examples of the lower alkyl group of the “lower alkyl group which may besubstituted” represented by R³ above include C₁₋₆ alkyl such as methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, neopentyl, hexyl, etc., and the like.

Examples of the lower alkoxy group of the “lower alkoxy group which maybe substituted” represented by R³ above include C₁₋₆ alkoxy such asmethoxy, ethoxy, propoxy, butoxy, etc., and the like.

Examples of the substituent which may be carried by the “lower alkylgroup which may be substituted” and “lower alkoxy group which may besubstituted” include halogen (for example, fluorine, chlorine, bromine,iodine), hydroxy group, amino, mono(lower alkyl)amino, di(loweralkyl)amino, lower alkanoyl and the like.

The lower alkyl carried by said mono(lower alkyl)amino and di(loweralkyl)amino may be exemplified by the same one as the lower alkyl groupof the “lower alkyl group which may be substituted” represented by R³above.

The lower alkanoyl may be exemplified by C₂₋₆ alkanoyl such as acetyl,propionyl, butyryl, isobutyryl or the like.

Among them, for R³, the lower C₁₋₆ alkyl group which may be substitutedis preferred, and particularly a methyl group which may be substitutedis preferred.

With respect to the above-described NR⁵R⁶ represented by R⁴, the“hydrocarbon group” of the “hydrocarbon group which may be substituted”represented by R⁵ and R⁶ may be exemplified by:

(1) alkyl (for example, C₁₋₁₀ alkyl such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower(C₁₋₆) alkyl, and more preferably lower (C₁₋₄) alkyl, or the like);

(2) cycloalkyl (for example, C₃₋₇ cycloalkyl such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., or the like);

(3) alkenyl (for example, alkenyl having 2 to 10 carbon atoms, such asallyl, crotyl, 2-pentenyl, 3-hexenyl, etc., and preferably lower (C₂₋₆)alkenyl, or the like);

(4) cycloalkenyl (for example, cycloalkenyl having 3 to 7 carbon atomssuch as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl,2-cyclohexenylmethyl, etc., or the like);

(5) alkynyl (for example, alkynyl having 2 to 10 carbon atoms, such asethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-pentynyl, 3-hexynyl, etc.,and preferably lower (C₂₋₆) alkynyl, or the like);

(6) aralkyl (for example, phenyl-C₁₋₄ alkyl (for example, benzyl,phenethyl, etc.) or the like);

(7) aryl (for example, phenyl, naphthyl, etc.);

(8) cycloalkyl-alkyl (for example, C₃₋₇ cycloalkyl-C₁₋₄ alkyl such ascyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cycloheptylmethyl, etc.); or the like.

Examples of the substituent which may be carried by the above-described(1) alkyl, (2) cycloalkyl, (3) alkenyl, (4) cycloalkenyl, (5) alkynyl,(6) aralkyl, (7) aryl and (8) cycloalkyl-alkyl, include halogen (forexample, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano,hydroxy group, thiol group which may be substituted (for example, thiol,C₁₋₄ alkylthio, etc.), amino group which may be substituted (forexample, amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- or6-membered cycloamino such as tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, etc.), carboxyl groupwhich may be esterified or amidated (for example, carboxyl, C₁₋₄alkoxycarbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, etc.), C₁₋₄ alkyl which may be halogenated (for example,trifluoromethyl, methyl, ethyl, etc.), C₁₋₄ alkoxy which may behalogenated (for example, methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy, etc.), C₁₋₄ alkylenedioxy (forexample, —O—CH₂—O—, —O—CH₂—CH₂—O—, etc.), sulfonamide which may besubstituted [for example, a group formed by bonding of an amino groupwhich may be substituted (for example, amino, mono-C₁₋₄ alkylamino,di-C₁₋₄ alkylamino, 5- or 6-membered cycloamino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc.) with —SO₂—, etc.], formyl, C₂₋₄ alkanoyl (forexample, acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (for example,methanesulfonyl, ethanesulfonyl, etc.), heterocyclic group which may besubstituted, and the like, and the number of the substituents ispreferably 1 to 3.

The “heterocyclic group” of said “heterocyclic group which may besubstituted” and the “heterocyclic group which may be substituted”represented by R⁴, may be exemplified by a group formed by eliminatingone hydrogen atom from an aromatic heterocycle or a non-aromaticheterocycle, or the like. Examples of such aromatic heterocycle include5- or 6-membered aromatic heterocycle containing 1 to 4 heteroatoms ofone or two kinds selected from nitrogen, sulfur and oxygen atoms, suchas furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole,isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine,pyridazine, triazole, oxadiazole, thiadiazole and the like, whileexamples of such non-aromatic heterocycle include 5- or 6-memberednon-aromatic heterocycle containing 1 to 4 heteroatoms of one or twokinds selected from nitrogen, sulfur and oxygen atoms, such astetrahydrofuran, tetrahydrothiophene, dioxolane, dithiolane,oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline,pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine,thiazine, thiadiazine, morpholine, thiomorpholine, pyran,tetrahydropyran, etc., and non-aromatic heterocycle in which all or partof the bonds in the above-mentioned aromatic heterocycles are saturatedbonds (preferably, aromatic heterocycle such as pyrazole, thiazole,oxazole, tetrazole, etc.).

With respect to the above-described NR⁵R⁶ represented by R⁴, thesubstituent of the “heterocyclic group” of the “heterocyclic group whichmay be substituted” represented by R⁵ and R⁶, may be exemplified by thesame substituent of the “hydrocarbon group” of the “hydrocarbon groupwhich may be substituted” represented by R^(4.)

The hydrocarbon group which may be substituted is preferably C₁₋₆ alkylwhich may be halogenated or hydroxylated, carboxyl which may beesterified or amidated, or C₂₋₆ alkenyl which may be halogenated orhydroxylated. With respect to the above-described NR⁵R⁶ represented byR⁴, the “acyl group which may be substituted” represented by R⁵ and R⁶may be exemplified by the same one as the “acyl group which may besubstituted” as the substituent which may be carried by the “5- or6-membered ring” of the “5- or 6-membered ring which may be substituted”represented by R¹, and among these, C₁₋₄ alkylsulfonyl which may behalogenated or hydroxylated, formyl, C₂₋₅ alkanoyl which may behalogenated or hydroxylated, and the like are preferred.

For R⁵ and R⁶, C₁₋₄ alkyl which may be halogenated or hydroxylated,formyl, C₂₋₅ alkanoyl which may be halogenated or hydroxylated, and thelike are more preferred, and propyl, isobutyl, isobutenyl or3-hydroxy-2-methylpropyl are particularly preferred. Another preferredembodiment of R⁵ and R⁶ may be exemplified by a group represented by theformula —(CH₂)_(s)—R^(x), wherein s is 0 or 1, and R^(x) is a 5- or6-membered ring which may be substituted (for example, those such as the“5- or 6-membered ring which may be substituted” represented by R¹,etc.; preferably phenyl, pyridyl, pyrazolyl, thiazolyl, oxazolyl,tetrazolyl, etc., each of which may be substituted with halogen, C₁₋₄alkyl which may be halogenated or hydroxylated, C₁₋₄ alkoxy which may behalogenated or hydroxylated, etc.), or the like.

Among these, R⁵ and R⁶ are preferably 1) C₁₋₆ alkyl, 2) C₂₋₆ alkenyl, 3)C₆₋₁₀ aryl, 4) C₆₋₁₀ aryl-methyl, 5) heterocyclic group and 6)heterocyclic methyl (wherein the above 1) and 2) may be substituted withhalogen, hydroxy group, or carboxyl group which may be esterified oramidated; and the above 3), 4), 5) and 6) may be substituted with C₁₋₆alkyl which may be substituted with halogen, hydroxy group, or carboxylgroup which may be esterified or amidated, or C₁₋₆ alkoxy which may besubstituted with halogen, hydroxy group, or carboxyl group which may beesterified or amidated).

With respect to the above-described NR⁵R⁶ represented by R⁴, theheterocyclic group which may be substituted, which is formed by NR⁵R⁶ asthe result of bonding of R⁵ and R⁶ may be exemplified by 4- to10-membered alicyclic cycloamino such as azetidinyl, pyrrolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, oxazolinyl, thiazolinyl,imidazolinyl, piperidinyl, morpholinyl, thiomorpholinyl,dihydropyridinyl, piperadinyl, azepinyl, oxazepinyl, thiazepinyl,diazepinyl, azocinyl, oxazocinyl, thiazocinyl, diazocinyl, etc.; 5- to10-membered aromatic cycloamino such as pyrrolyl, imidazolyl, triazolyl,tetrazolyl, etc. (preferably 5- to 8-membered alicyclic cycloamino, morepreferably 5-membered alicyclic cycloamino such as pyrrolidinyl, etc.),or the like. These cycloamino groups may be substituted, and examples ofsuch substituent include halogen (for example, fluorine, chlorine,bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group whichmay be substituted (for example, thiol, C₁₋₄ alkylthio, etc.), aminogroup which may be substituted (for example, amino, mono-C₁₋₄alkylamino, di-C₁₋₄ alkylamino, 5- or 6-membered cycloamino such aspyrrolidine, piperidine, piperazine, morpholine, thiomorpholine,pyrrole, imidazole, etc., or the like), carboxyl group which may beesterified or amidated [for example, carboxyl, C₁₋₄ alkoxycarbonyl (forexample, methoxycarbonyl, ethoxycarbonyl, etc.), carbamoyl, mono-C₁₋₄alkylcarbamoyl (for example, methylcarbamoyl, ethylcarbamoyl, etc.),di-C₁₋₄ alkylcarbamoyl (for example, dimethylcarbamoyl,diethylcarbamoyl, ethylmethylcarbamoyl, etc.), etc.], C₁₋₄ alkyl whichmay be substituted (for example, in addition to methyl, ethyl, propyl,etc., halogenated alkyl such as trifluoromethyl, for example, C₂₋₃alkanoyloxy-C₁₋₃ alkyl such as acetyloxymethyl, propionyloxymethyl,acetyloxyethyl, propionyloxyethyl, etc., for example, C₁₋₄ hydroxyalkylsuch as hydroxymethyl, hydroxyethyl, etc.), C₁₋₄ alkoxy which may besubstituted (for example, methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy, carboxy-C₁₋₄ alkoxy, carbamoyl-C₁₋₄alkoxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, etc.), formyl, C₂₋₄alkanoyl (for example, acetyl, propionyl, etc.), C₁₋₄ alkylsulfonyl (forexample, methanesulfonyl, ethanesulfonyl, etc.), C₁₋₃ alkylenedioxy (forexample, methylenedioxy, ethylenedioxy, etc.), oxo group which may beacetalized (C₁₋₄ dialkoxy, 1,3-diodisolane, 1,3-dioxane, etc.), or thelike. The number of the substituents is preferably 1 to 3.

The lower alkyl group of the “lower alkyl group which may besubstituted” represented by each of the above-described R⁷ and R⁸, maybe exemplified by C₁₋₆ alkyl such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,hexyl, etc., or the like.

Examples of the substituent which may be carried by said “lower alkylgroup which may be substituted” and “lower alkoxy group which may besubstituted” include halogen (for example, fluorine, chlorine, bromine,iodine), hydroxy group, amino, mono(lower alkyl)amino, di(loweralkyl)amino, lower alkanoyl or the like.

The lower alkyl carried by said mono(lower alkyl)amino and di(loweralkyl)amino may be exemplified by the same lower alkyl group of the“lower alkyl group which may be substituted” represented by each of theabove-described R⁷ and R^(8.)

Examples of the lower alkanoyl include C₂₋₆ alkanoyl such as acetyl,propionyl, butyryl, isobutyryl and the like.

Among them, each of R⁷ and R⁸ is preferably lower C₁₋₆ alkyl group whichmay be substituted, and particularly preferably methyl group which maybe substituted.

With respect to CR represented by the above-described X, the lower alkylgroup of the “lower alkyl group which may be substituted” represented byR may be exemplified by C₁₋₆ alkyl such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl, hexyl or the like.

For CR represented by the above-described X, the lower alkoxy group ofthe “lower alkoxy group which may be substituted” represented by R maybe exemplified by C₁₋₆ alkoxy such as methoxy, ethoxy, propoxy, butoxyor the like.

Examples of the substituent which may be carried by said “lower alkylgroup which may be substituted” and “lower alkoxy group which may besubstituted” include halogen (for example, fluorine, chlorine, bromine,iodine), hydroxy group, amino, mono(lower alkyl)amino, di(loweralkyl)amino, lower alkanoyl and the like.

The lower alkyl of said mono(lower alkyl)amino and di(lower alkyl)aminomay be exemplified by the same lower alkyl group as the “lower alkylgroup which may be substituted” represented by the above-describedR^(3.)

Examples of said lower alkanoyl include C₂₋₆ alkanoyl such as acetyl,propionyl, butyryl, isobutyryl and the like.

With respect to CR represented by the above-described X, the “acyl groupwhich may be substituted” represented by R may be exemplified by thesame one as the “acyl group which may be substituted” as the substituentwhich may be carried by the “5- or 6-membered ring” of the “5- or6-membered ring which may be substituted” represented by R¹, and amongthem, preferred are C₁₋₄ alkylsulfonyl which may be halogenated orhydroxylated, formyl, C₂₋₅ alkanoyl which may be halogenated orhydroxylated, and the like.

Among them, for R, lower C₁₋₆ alkyl group which may be substituted ispreferred, and in particular, methyl group which may be substituted ispreferred.

The 5- or 6-membered alicyclic heterocycle which is formed by bonding ofX and R⁴, may be exemplified by pyrrolidine, oxazolidine, thiazolidine,imidazolidine, piperidine, morpholine, thiomorpholine, piperazine or thelike. These may be substituted at any arbitrary positions on the ring,and examples of the substituent include those described as thesubstituents of the “5- or 6-membered ring” with respect to the “5- or6-membered ring which may be substituted” represented by R^(1.)

In the above formula (I), the “5- or 6-membered aromatic ring which maybe substituted” represented by Z¹ may be exemplified by 6-memberedaromatic hydrocarbon such as benzene; 5- to 6-membered aromaticheterocycle containing 1 to 4 heteroatoms of one or two kinds selectedfrom nitrogen, sulfur and oxygen atoms, such as furan, thiophene,pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole,tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, etc.;fused aromatic heterocycle such as benzofuran, indole, benzothiophene,benzoxazole, benzothiazole, indazole, benzimidazole, quinoline,isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline,imidazopyridine, etc.; or the like. Among them, preferred are benzene,furan, thiophene, pyridine, pyridazine, pyrimidine, benzimidazole andthe like, and particularly preferably used are benzene, pyridine,pyridazine and benzimidazole (preferably benzene).

The “5- or 6-membered aromatic ring which may be substituted”represented by Z¹ may have the same substituent as the “substituent”which may be carried by the “5- or 6-membered ring” of the “5- or6-membered ring which may be substituted” represented by R¹, and amongthe substituents, a halogen atom (for example, fluorine, chlorine,bromine, etc.), a C₁₋₄ alkyl group which may be substituted with halogenatom(s) (for example, methyl, ethyl, trifiluoromethyl, trifluoroethyl,etc.), a C₁₋₄ alkoxy group which may be substituted with halogen atom(s)(for example, methoxy, ethoxy, propoxy, trifluoromethoxy,trifluoroethoxy, etc.) and the like are preferred. However, it ispreferred that there is no other substituent than X² and Z², and it ispreferred that when Z¹ is a 6-membered ring (preferably benzene), theposition of substitution of Z² is para to X². Further, for thesubstituent of Z¹, benzene which may be substituted with 1) a halogenatom, 2) a C₁₋₄ alkyl group which may be substituted with halogenatom(s), or 3) a C₁₋₄ alkoxy group which may be substituted with halogenatom(s) is preferred, and in particular, benzene which may besubstituted with methyl or trifluoromethyl is preferred.

In the above formula (I), with respect to the formula -Z^(2a)-W¹-Z^(2b)-and -Z^(2a)-W²-Z^(2b)- represented by Z², the substituent (R^(a)) of the“imino group which may be substituted” represented by each of Z^(2a) andZ^(2b) may be exemplified by hydrogen atom, lower (C₁₋₆) alkyl which maybe substituted [for example, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl,hydroxy-C₁₋₆ alkyl (for example, hydroxyethyl, hydroxypropyl,hydroxybutyl, etc.), halogenated C₁₋₆ alkyl (for example,trifluoromethyl, trifluoroethyl, etc.), cyanated C₁₋₆ alkyl (forexample, cyanoethyl, cyanopropyl, etc.), carboxyl-C₁₋₆ alkyl which maybe esterified or amidated, etc.], formyl, lower (C₂₋₅) alkanoyl (forexample, acetyl, propionyl, butyryl, etc.), lower (C₁₋₅) alkylsulfonyl(methylsulfonyl, ethylsulfonyl, etc.), or the like.

The alkylene chain of the “alkylene group which may be substituted”represented by W¹ and W² may be exemplified by the alkylene chainrepresented by —(CH₂)_(k1)— (wherein k1 is an integer of 1 to 4) or thelike. The alkenylene group of the “alkenylene group which may besubstituted” represented by W¹ may be exemplified by the alkenylenechain represented by —(CH₂)_(k2)—(CH═CH)—(CH₂)_(k3)— (wherein k2 and k3are identical or different, and represent 0, 1 or 2, respectively,provided that the sum of k2 and k3 is 2 or less) or the like. Thealkylene group and alkenylene group represented by said W¹ and W² may besubstituted at any arbitrary position (preferably on a carbon atom), andsuch substituent may be any substituent capable of bonding to thealkylene chain or alkenylene chain which constitutes the straight chainmoiety. Examples thereof include lower (C₁₋₆) alkyl (for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.), lower(C₃₋₇)cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, etc.), formyl, lower (C₂₋₇) alkanoyl, (forexample, acetyl, propionyl, butyryl, etc.), phosphono which may beesterified, carboxyl which may be esterified or amidated, hydroxy group,oxo, hydroxyimino group, lower (C₁₋₆) alkoxyimino group which may besubstituted, and the like, and preferably lower alkyl having 1 to 6carbon atoms (preferably, C₁₋₃ alkyl), hydroxy group, oxo, hydroxyiminogroup, lower (C₁₋₆) alkoxyimino group (which may be substituted with apolar group such as hydroxy group, cyano group, carboxyl group which maybe esterified or amidated (for example, carboxyl, C₁₋₄ alkoxycarbonyl,carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.),etc.) or the like.

The phosphono group which may be esterified may be exemplified by agroup represented by P(O)(OR¹²) (OR¹³), wherein R¹² and R¹³ are eachhydrogen, an alkyl group having 1 to 6 carbon atoms, or a cycloalkylgroup having 3 to 7 carbon atoms, or R¹² and R¹⁰ may be bonded to eachother to form a 5- to 7-membered ring.

In the above-described formula, the alkyl group having 1 to 6 carbonatoms represented by R¹² and R¹³ may be exemplified by methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, hexyl or the like, and the cycloalkyl having 3 to7 carbon atoms may be exemplified by cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or the like. Preferred is linearlower alkyl having 1 to 6 carbon atoms, and more preferred is loweralkyl having 1 to 3 carbon atoms. R¹² and R¹³ may be identical with ordifferent from each other, and preferably identical. When R¹² and R¹³are bonded to each other to form a 5- to 7-membered ring, R¹² and R¹³are bonded to each other to form a linear C₂₋₄ alkylene side chainrepresented by —(CH₂)₂—, —(CH₂)₃— or —(CH₂)₄—. This side chain may besubstituted, and examples of such substituent include hydroxy group,halogen and the like.

The ester product of the above-described carboxyl group which may beesterified may be exemplified by a product resulting from bondingbetween a carboxyl group and an alkyl group having 1 to 6 carbon atomsor a cycloalkyl group having 3 to 7 carbon atoms, for example,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl,cyclopentyloxycarbonyl, cyclohexyloxycarbonyl or the like.

The amide product of the above-described carboxyl group which may beamidated may be exemplified by a product resulting from bonding betweena carboxyl group and an alkylamino group having 1 to 6 carbon atoms, acycloalkylamino group having 3 to 7 carbon atoms or a 5- to 8-memberedcyclic amine (for example, pyrrolidine, piperidine, morpholine, etc.),for example, carbamoyl, mono-C₁₋₆ alkylcarbamoyl, di-C₁₋₆alkylcarbamoyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl,pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl,thiomorpholinocarbonyl or the like.

For Z² preferably, one of Z^(2a) and Z^(2b) is O, S(O)_(m) (wherein m isan integer of 0, 1 or 2), or —N(R^(a))— (wherein R^(a) is a hydrogenatom or a lower C₁₋₄ alkyl group which may be substituted), the otherbeing a bond, and W is —(CH₂)_(p)— (wherein p is an integer of 1 to 3),or Z² is a divalent group of the formula —CH(OH)—. More preferably, oneof Z^(2a) and Z^(2b) is O or S(O)_(m) (wherein m is an integer of 0, 1or 2), the other being a bond, and W is —(CH₂)_(p)— (wherein p is aninteger of 1 to 3), or Z² is a divalent group of the formula —CH(OH)—.Even more preferably, Z² is —CH₂—, —CH(OH)—, —S(O)_(m)—CH₂— (wherein mis 0, 1 or 2), with —S(O)_(n)—CH₂— (wherein m is 0, 1 or 2) beingparticularly preferred. In particular, when Z^(2a) is bonded to Z¹, Z²is preferably —SOCH₂—.

Z^(2a) represents a bond, S, SO or SO₂, and among them, SO is preferred.In this case, the configuration of SO is preferably (S).

The bonding position of Z² with respect to Z¹ is such that when Z¹ is abenzene ring for example, any position may be selected, but the paraposition is preferred.

In the above formula (I), the “amino group which may be substituted, inwhich the nitrogen atom may be converted to a quaternary ammonium or anoxide” represented by R² may be exemplified by an amino group which mayhave 1 or 2 substituents, an amino group which has three substituents,in which the nitrogen atom is converted to a quaternary ammonium, or thelike. When the amino group has two or more substituents on its nitrogenatom, the substituents may be identical or different; and when thenitrogen atom has 3 substituents, the amino group may be of any typeamong the following formulas, —N⁺R^(p)R^(p)R^(p), —N⁺R^(p)R^(p)R^(q),and —N⁺R^(p)R^(q)R^(r), wherein R^(p), R^(q), and R^(r) are differentfrom each other, each being hydrogen or a substituent. Examples of thecounter anion of the amino group, in which the nitrogen atom isconverted to a quaternary ammonium include, in addition to anions ofhalogen (for example, Cl⁻, Br⁻, I⁻, etc.), anions derived from inorganicacids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid, etc.; anions derived from organic acids such asformic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, etc.; and anions derived from acidic amino acids such as asparticacid, glutamic acid, etc., and among them, Cl⁻, Br⁻, I⁻ and the like arepreferred.

Examples of the substituent of said amino group include:

(1) alkyl which may be substituted (for example, C₁₋₁₀ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., and preferably lower (C₁₋₆) alkyl, or the like); and

(2) cycloalkyl which may be substituted (for example, C₃₋₈ cycloalkylsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyanooctyl, etc., or the like);

(2-1) the cycloalkyl may contain one heteroatom selected from sulfur,oxygen and nitrogen atoms, forming oxirane, thiolane, aziridine,tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran,tetrahydrothiopyran, tetrahydrothiopyran 1-oxide, piperidine, etc.(preferably, a 6-membered ring such as tetrahydropyran,tetrahydrothiopyran, piperidine, etc.), and the bond with the aminogroup is preferably present at the 3- or 4-position (preferably, at the4-position);

(2-2) also, the cycloalkyl may be fused to a benzene ring, formingindane (for example, indan-1-yl, indan-2-yl, etc.),tetrahydronaphthalene (for example, tetrahydronaphthalen-5-yl,tetrahydronaphthalen-6-yl, etc.), or the like (preferably, indane,etc.);

(2-3) further, the cycloalkyl may be bridged via a straight atomic chainhaving 1 or 2 carbon atoms, forming a bridged cyclic hydrocarbon residuesuch as bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl,bicyclo[3.2.2]nonyl, etc. (preferably, cyclohexyl bridged via a straightatomic chain having 1 to 2 carbon atoms, and more preferably,bicyclo[2.2.1]heptyl, etc.);

(3) alkenyl which may be substituted (for example, alkenyl having 2 to10 carbon atoms, such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., andpreferably lower (C₂₋₆) alkenyl, or the like);

(4) cycloalkenyl which may be substituted (for example, cycloalkenylhaving 3 to 7 carbon atoms, such as 2-cyclopentenyl, 2-cyclohexenyl,2-cyclopentenylmethyl, 2-cylcohexenylmethyl, etc., or the like);

(5) aralkyl which may be substituted (for example, phenyl-C₁₋₄ alkyl(for example, benzyl, phenethyl, etc.), or the like);

(6) formyl, or acyl which may be substituted (for example, alkanoylhaving 2 to 4 carbon atoms (for example, acetyl, propionyl, butyryl,isobutyryl, etc.), alkylsulfonyl having 1 to 4 carbon atoms (forexample, methanesulfonyl, ethanesulfonyl, etc.), alkoxycarbonyl having 1to 4 carbon atoms (for example, methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl, etc.), aralkyloxycarbonyl having 7 to 10 carbonatoms (for example, benzyloxycarbonyl, etc.), or the like);

(7) aryl which may be substituted (for example, phenyl, naphthyl, etc.);

(8) heterocyclic group which may be substituted (for example, a groupformed by eliminating a hydrogen atom from a 5- or 6-membered aromaticheterocycle containing 1 to 4 heteroatoms of one or two kinds selectedfrom nitrogen, sulfur and oxygen atoms, such as furan, thiophene,pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole,tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole,oxadiazole, thiadiazole, etc., or from a fused heterocyclic aromaticgroup such as benzofuran, indole, benzothiophene, benzoxazole,benzothiazole, indazole, benzimidazole, quinoline, isoquinoline,quinoxaline, phthalazine, quinazoline, cinnoline, imidazopyridine, etc.;a group formed by eliminating a hydrogen atom from a 5- or 6-memberednon-aromatic heterocycle containing 1 to 4 heteroatoms of one or twokinds selected from nitrogen, sulfur and oxygen atoms, such astetrahydrofuran, tetrahydrothiophene, dithiolane, oxathiolane,pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine,pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine,thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran, etc.;or the like; and preferably, a group formed by eliminating a hydrogenatom from a 5- or 6-membered non-aromatic heterocycle; more preferably,a group formed by eliminating a hydrogen atom from a 5- or 6-memberednon-aromatic heterocycle containing one heteroatom, such astetrahydrofuran, piperidine, tetrahydropyran, tetrahydrothiopyran,etc.); and the like. The substituents on the amino group may be bondedto each other to form 5- to 7-membered cycloamino such as piperidine,piperazine, morpholine, thiomorpholine, etc.

Examples of the substituent which may be carried by the above-described(1) alkyl which may be substituted, (2) cycloalkyl which may besubstituted, (3) alkenyl which may be substituted, (4) cycloalkenylwhich may be substituted, (5) aralkyl which may be substituted, (6) acylwhich may be substituted, (7) aryl which may be substituted, and (8)heterocyclic group which may be substituted, include halogen (forexample, fluorine, chlorine, bromine, iodine, etc.); lower (C₁₋₄) alkylwhich may be halogenated; lower (C₁₋₄) alkyl which may be substitutedwith a polar group such as a hydroxy group, a cyano group, a carboxylgroup which may be esterified or amidated, etc. (for example,hydroxy-C₁₋₄ alkyl, cyano-C₁₋₄ alkyl, carboxy-C₁₋₄ alkyl, C₁₋₄alkoxycarbonyl-C₁₋₄ alkyl, carbamoyl-C₁₋₄ alkyl, mono-C₁₋₄alkylcarbamoyl-C₁₋₄ alkyl, di-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl-C₁₋₄ alkyl, pyrrolidinocarbonyl-C₁₋₄ alkyl,piperidinocarbonyl-C₁₋₄ alkyl, morpholinocarbonyl-C₁₋₄ alkyl,thiomorpholinocarbonyl-C₁₋₄ alkyl, etc.); C₁₋₄ alkoxy which may behalogenated (for example, methoxy, ethoxy, propoxy, butoxy,trifluoromethoxy, trifluoroethoxy, etc.); C₁₋₄ alkylenedioxy (forexample, —O—CH₂—O—, —O—CH₂—CH₂—O—, etc.); formyl; C₂₋₄ alkanoyl (forexample, acetyl, propionyl, etc.); C₁₋₄ alkylsulfonyl (for example,methanesulfonyl, ethanesulfonyl, etc.); phenyl-lower (C₁₋₄) alkyl; C₃₋₇cycloalkyl; cyano; nitro; hydroxy group; thiol group which may besubstituted (for example, thiol, C₁₋₄ alkylthio, etc.); amino groupwhich may be substituted (for example, amino, mono-C₁₋₄ alkylamino,di-C₁₋₄ alkylamino, 5- or 6-membered cycloamino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc.); carboxyl group which may be esterified oramidated (for example, carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl,mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.); lower (C₁₋₄)alkoxycarbonyl; lower (C₇₋₁₀) aralkyloxy-carbonyl; oxo group(preferably, halogen, lower (C₁₋₄) alkyl which may be halogenated, lower(C₁₋₄) alkoxy which may be halogenated, phenyl-lower (C₁₋₄) alkyl, C₃₋₇cycloalkyl, cyano, hydroxy group, etc); and the like. The number of thesubstituents is preferably 1 to 3.

In the above formula (I), the “amino group which may be substituted, inwhich the nitrogen atom may be converted to a quaternary ammonium or anoxide” represented by R² is preferably an amino group which may have 1to 3 substituents selected from:

(1) linear or branched lower (C₁₋₆) alkyl which may be substituted withone to three of halogen, cyano, hydroxy group or C₃₋₇ cycloalkyl;

(2) C₅₋₈ cycloalkyl which may be substituted with one to three ofhalogen, lower (C₁₋₄) alkyl which may be halogenated, or phenyl-lower(C₁₋₄) alkyl, which may contain one heteroatom selected from sulfur,oxygen and nitrogen atoms, which may be fused to a benzene ring, andwhich may be bridged via a straight atomic chain having 1 or 2 carbonatoms (for example, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,tetrahydropyranyl, tetrahydrothiapyranyl, piperidinyl, indanyl,tetrahydronaphthalenyl, bicyclo[2.2.1]heptyl, etc., each of which may besubstituted);

(3) phenyl-lower (C₁₋₄) alkyl which may have one to three of halogen,lower (C₁₋₄) alkyl which may be halogenated, or lower (C₁₋₄) alkoxywhich may be halogenated;

(4) phenyl which may have one to three of halogen, lower (C₁₋₄) alkylwhich may be halogenated, or lower (C₁₋₄) alkoxy which may behalogenated; and

(5) 5- to 6-membered aromatic heterocyclic group which may have one tothree of halogen, lower (C₁₋₄) alkyl which may be halogenated, lower(C₁₋₄) alkoxy groups which may be halogenated, lower (C₁₋₄) alkoxy-lower(C₁₋₄) alkoxy which may be halogenated, phenyl-lower (C₁₋₄) alkyl, cyanoor hydroxy group (for example, a group formed by eliminating onehydrogen atom from furan, thiophene, pyrrole, pyridine, etc.).

In the above formula (I), the “nitrogen-containing heterocyclic group”of the “nitrogen-containing heterocyclic group which may be substituted,which may contain a sulfur atom or an oxygen atom as thering-constituting atom, in which the nitrogen atom may be converted to aquaternary ammonium or an oxide” represented by R², may be exemplifiedby 5- to 6-membered aromatic heterocycle containing 1 to 4 heteroatomsof one or two kinds selected from nitrogen, sulfur and oxygen atoms,such as pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole,isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine,triazole, oxadiazole, thiadiazole, etc.; fused aromatic heterocycle suchas benzofuran, indole, benzothiophene, benzoxazole, benzothiazole,indazole, benzimidazole, quinoline, isoquinoline, quinoxaline,phthalazine, quinazoline, cinnoline, imidazopyridine, etc.; 5- to8-membered non-aromatic heterocycle containing a nitrogen atom andadditionally 1 to 3 heteroatoms of one or two kinds selected fromnitrogen, sulfur and oxygen atoms, such as pyrrolidine, pyrroline,imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine,piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine,thiomorpholine, azacycloheptane, azacyclooctane (azocane), etc.; or thelike, and these nitrogen-containing heterocycles may be bridged via astraight atomic chain having 1 or 2 carbon atoms, forming a bridged-ringnitrogen-containing heterocycle such as azabicyclo[2.2.1]heptane,azabicyclo[2.2.2]octane (quinuclidine), etc. (preferably, piperidinebridged via a straight atomic chain having 1 or 2 carbon atoms, etc.).

Among specific examples of the above-described nitrogen-containingheterocycle, preferred are pyridine, pyridazine, pyrazole, imidazole,triazole, tetrazole, imidazopyridine, pyrrolidine, piperidine,piperazine, morpholine, thiomorpholine and azabicyclo[2.2.2]octane(preferably, pyridine, imidazole, triazole, imidazopyridine,pyrrolidine, piperidine and morpholine).

The nitrogen atom of the “nitrogen-containing heterocycle” may beconverted to a quaternary ammonium or may be oxidized. When the nitrogenatom of the “nitrogen-containing heterocycle” is conveted to aquaternary ammonium, the counter anion of the “nitrogen-containingheterocyclic group in which the nitrogen atom is converte to aquaternary ammonium” may be exemplified by, in addition to anions ofhalogen (for example, Cl⁻, Br⁻, I⁻, etc.), anions derived from inorganicacids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid, phosphoric acid, etc.; anions derived from organic acids such asformic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, etc.; anions derived from acidic amino acids such as asparticacid, glutamic acid, etc.; or the like, and among them, Cl⁻, Br⁻, I⁻ andthe like are preferred.

The “nitrogen-containing heterocyclic group” may be bonded to a divalentgroup represented by Z² via a carbon atom or a nitrogen atom, and may bebonded to a ring-constituting carbon atom as in 2-pyridyl, 3-pyridyl,2-piperidinyl, etc., or to a ring-constituting nitrogen atom as in thefollowing:

The substituent which may be carried by the “nitrogen-containingheterocycle” may be exemplified by halogen (for example, fluorine,chlorine, bromine, iodine, etc.), lower (C₁₋₄) alkyl which may besubstituted, lower (C₁₋₄) alkoxy which may be substituted, phenyl whichmay be substituted, mono- or diphenyl-lower (C₁₋₄) alkyl which may besubstituted, C₃₋₇ cycloalkyl which may be substituted, cyano, nitro,hydroxy group, thiol group which may be substituted (for example, thiol,C₁₋₄ alkylthio, etc.), amino group which may be substituted (forexample, amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- to6-membered cycloamino such as tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, etc.), carboxyl groupwhich may be esterified or amidated (for example, carboxyl, C₁₋₄alkoxycarbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄alkylcarbamoyl, etc.), lower (C₁₋₄) alkoxy-carbonyl, formyl, lower(C₂₋₄) alkanoyl, lower (C₁₋₄) alkylsulfonyl, heterocyclic group whichmay be substituted (for example, a group formed by eliminating ahydrogen atom from a 5- to 6-membered aromatic heterocycle containing 1to 4 heteroatoms of one or two kinds selected from nitrogen, sulfur andoxygen atoms, such as furan, thiophene, pyrrole, imidazole, pyrazole,thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine,pyrazine, pyrimidine, pyridazine, triazole, oxadiazole, thiadiazole,etc., or from a fused aromatic heterocyclic group containing 1 to 4heteroatoms of one or two kinds selected from nitrogen, sulfur andoxygen atoms, such as benzofuran, indole, benzothiophene, benzoxazole,benzothiazole, indazole, benzimidazole, quinoline, isoquinoline,quinoxaline, phthalazine, quinazoline, cinnoline, imidazopyridine, etc.;a group formed by eliminating a hydrogen atom from a 5- to 6-memberednon-aromatic heterocycle containing 1 to 4 heteroatoms of one or twokinds selected from nitrogen, sulfur and oxygen atoms, such astetrahydrofuran, tetrahydrothiophene, dithiolane, oxathiolane,pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine,pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine,thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran,tetrahydrothiopyran, etc.), or the like, and the number of thesubstituents is preferably 1 to 3. The nitrogen atom in thenitrogen-containing heterocyclic ring may be oxidized.

Examples of the substituent which may be carried respectively by the“lower (C₁₋₄) alkyl which may be substituted”, the “lower (C₁₋₄) alkoxywhich may be substituted”, the “phenyl which may be substituted”, the“mono- or diphenyl-lower (C₁₋₄) alkyl which may be substituted”, the“C₃₋₇ cycloalkyl which may be substituted”, and the “heterocyclic groupwhich may be substituted”, all of which are the substituents that may becarried by the “nitrogen-containing heterocycle”, include halogen atom(for example, fluorine, chlorine, bromine, iodine, etc.); lower (C₁₋₄)alkyl which may be halogenated; lower (C₁₋₄) alkyl which may besubstituted by a polar group such as a hydroxy group, a cyano group, acarboxyl group which may be esterified or amidated, etc. (for example,hydroxy-C₁₋₄ alkyl, cyano-C₁₋₄ alkyl, carboxy-C₁₋₄ alkyl, C₁₋₄alkoxycarbonyl-C₁₋₄ alkyl, carbamoyl-C₁₋₄ alkyl, mono-C₁₋₄alkylcarbamoyl-C₁₋₄ alkyl, di-C₁₋₄ alkylcarbamoyl-C₁₋₄ alkyl,pyrrolidinocarbonyl-C₁₋₄ alkyl, piperidinocarbonyl-C₁₋₄ alkyl,morpholinocarbonyl-C₁₋₄ alkyl, thiomorpholinocarbonyl-C₁₋₄ alkyl, etc.);lower (C₃₋₁₀) cycloalkyl; lower (C₃₋₁₀) cycloalkenyl; C₁₋₄ alkoxy whichmay be halogenated (for example, methoxy, ethoxy, trifluoromethoxy,trifluoroethoxy, etc.); formyl; C₂₋₄ alkanoyl (for example, acetyl,propionyl, etc.); C₁₋₄ alkylsulfonyl (for example, methanesulfonyl,ethanesulfonyl, etc.); C₁₋₃ alkylenedioxy (for example, methylenedioxy,ethylenedioxy, etc.); cyano; nitro; hydroxy group; thiol group which maybe substituted (for example, thiol, C₁₋₄ alkylthio, etc.); amino groupwhich may be substituted (for example, amino, mono-C₁₋₄ alkylamino,di-C₁₋₄ alkylamino, 5-to 6-membered cycloamino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc.); carboxyl group which may be esterified oramidated (for example, carboxyl, C₁₋₄ alkoxy-carbonyl, carbamoyl,mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.); lower (C₁₋₄)alkoxycarbonyl; and the like, and the number of the substituents ispreferably 1 to 3.

In the above formula (I), the substituent which may be carried by the“nitrogen-containing heterocyclic group” of the “nitrogen-containingheterocyclic group which may be substituted and may contain a sulfuratom or an oxygen atom as the ring-constituting atom, in which thenitrogen atom may be converted to a quaternary ammonium or an oxide” ispreferably (1) halogen, (2) cyano, (3) hydroxy group, (4) carboxylgroup, (5) carbamoyl, (6) lower (C₁₋₄) alkoxycarbonyl, (7) lower (C₁₋₄)alkylcarbamoyl, or 5- or 6-membered cycloamino (piperidino, morpholino,etc.)-carbonyl, (8) lower (C₁₋₄) alkyl which may be substituted withhalogen, hydroxy group, cyano group, lower (C₁₋₄) alkoxy, or carboxylwhich may be esterified or amidated, (9) lower (C₁₋₄) alkoxy which maybe substituted with halogen, hydroxy group or lower (C₁₋₄) alkoxy, (10)phenyl which may be substituted with halogen, lower (C₁₋₄) alkyl,hydroxy group, lower (C₁₋₄) alkoxy or C₁₋₃ alkylenedioxy, (11) mono- ordiphenyl-lower (C₁₋₄) alkyl which may be substituted with halogen, lower(C₁₋₄) alkyl, hydroxy group, lower (C₁₋₄) alkoxy or C₁₋₃ alkylenedioxy,or (12) a group formed by eliminating a hydrogen atom from a 5- or6-membered aromatic heterocycle such as furan, thiophene, pyrrole,pyridine, etc., or the like.

In the above formula (I), with respect to the group represented byformula (a) represented by R², the “hydrocarbon group which may besubstituted” represented by R⁹ and R¹⁰ may be exemplified by:

(1) alkyl which may be substituted (for example, C₁₋₁₀ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., and preferably lower (C₁₋₆) alkyl, or the like);

(2) cycloalkyl which may be substituted (for example, C₃₋₇ cycloalkylsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,etc., or the like);

(3) alkenyl which may be substituted (for example, alkenyl having 2 to10 carbon atoms, such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., andpreferably lower (C₂₋₆) alkenyl, or the like);

(4) cycloalkenyl which may be substituted (for example, cycloalkenylhaving 3 to 7 carbon atoms, such as 2-cyclopentenyl, 2-cyclohexenyl,2-cyclopentenylmethyl, 2-cylcohexenylmethyl, etc., or the like);

(5) alkynyl which may be substituted (for example, alkynyl having 2 to10 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,2-pentynyl, 3-hexynyl, etc., and preferably lower (C₂₋₆) alkynyl, or thelike);

(6) aralkyl which may be substituted (for example, phenyl-C₁₋₄ alkyl(for example, benzyl, phenethyl, etc.) or the like);

(7) aryl which may be substituted (for example, phenyl, naphthyl, etc.);or the like. Examples of the substituents which may be carried by theabove-described (1) alkyl which may be substituted, (2) cycloalkyl whichmay be substituted, (3) alkenyl which may be substituted, (4)cycloalkenyl which may be substituted, (5) alkynyl which may besubstituted, (6) aralkyl which may be substituted, and (7) aryl whichmay be substituted, include halogen (for example, fluorine, chlorine,bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group whichmay be substituted (for example, thiol, C₁₋₄ alkylthio, etc.), aminogroup which may be substituted (for example, amino, mono-C₁₋₄alkylamino, di-C₁₋₄ alkylamino, 5- to 6-membered cycloamino such astetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine,pyrrole, imidazole, etc.), carboxyl group which may be esterified oramidated (for example, carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl,mono-C₁₋₄ alkylcarbamoyl, di-C₁₋₄ alkylcarbamoyl, etc.), C₁₋₄ alkylwhich may be halogenated (for example, trifluoromethyl, methyl, ethyl,etc.), C₁₋₄ alkoxy which may be halogenated (for example, methoxy,ethoxy, propoxy, butoxy, trifluoromethoxy, trifluoroethoxy, etc.),formyl, C₂₋₄ alkanoyl (for example, acetyl, propionyl, etc.), C₁₋₄alkylsulfonyl (for example, methanesulfonyl, ethanesulfonyl, etc.), andthe like, and the number of the substituents is preferably 1 to 3.

The “hydroxy group which may be substituted” represented by R⁹ and R¹⁰may be exemplified by a hydroxy group which may have:

(1) alkyl which may be substituted (for example, C₁₋₁₀ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., and preferably lower (C₁₋₆) alkyl, or the like);

(2) cycloalkyl which may be substituted (for example, C₃₋₇ cycloalkylsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,etc., or the like);

(3) alkenyl which may be substituted (for example, alkenyl having 2 to10 carbon atoms, such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., andpreferably lower (C₂₋₆) alkenyl, or the like);

(4) cycloalkenyl which may be substituted (for example, cycloalkenylhaving 3 to 7 carbon atoms, such as 2-cyclopentenyl, 2-cyclohexenyl,2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc., or the like);

(5) aralkyl which may be substituted (for example, phenyl-C₁₋₄ alkyl(for example, benzyl, phenethyl, etc.), or the like);

(6) formyl, or acyl which may be substituted (for example, alkanoylhaving 2 to 4 carbon atoms (for example, acetyl, propionyl, butyryl,isobutyryl, etc.), alkylsulfonyl having 1 to 4 carbon atoms (forexample, methanesulfonyl, ethanesulfonyl, etc.), or the like);

(7) aryl which may be substituted (for example, phenyl, naphthyl, etc.);or the like.

Examples of the substituent which may be carried by the above-described(1) alkyl which may be substituted, (2) cycloalkyl which may besubstituted, (3) alkenyl which may be substituted, (4) cycloalkenylwhich may be substituted, (5) aralkyl which may be substituted, (6) acylwhich may be substituted, and (7) aryl which may be substituted, includehalogen (for example, fluorine, chlorine, bromine, iodine, etc.), nitro,cyano, hydroxy group, thiol group which may be substituted (for example,thiol, C₁₋₄ alkylthio, etc.), amino group which may be substituted (forexample, amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- to6-membered cycloamino such as tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, etc., or the like),carboxyl group which may be esterified or amidated (for example,carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl,di-C₁₋₄ alkylcarbamoyl, etc.), C₁₋₄ alkyl which may be halogenated (forexample, trifluoromethyl, methyl, ethyl, etc.), C₁₋₄ alkoxy which may behalogenated (for example, methoxy, ethoxy, trifluoromethoxy,trifluoroethoxy, etc.), formyl, C₂₋₄ alkanoyl (for example, acetyl,propionyl, etc.), C₁₋₄ alkylsulfonyl (for example, methanesulfonyl,ethanesulfonyl, etc.), and the like; and the number of the substituentsis preferably 1 to 3.

Further, in the above-described formula, R⁹ and R¹⁰ may be bonded toeach other to form a cyclic group (preferably, 5- to 7-membered ring)together with the adjacent phosphorus atom. Such cyclic group may besubstituted, and examples of the substituents include halogen (forexample, fluorine, chlorine, bromine, iodine, etc.), nitro, cyano,hydroxy group, thiol group which may be substituted (for example, thiol,C₁₋₄ alkylthio, etc.), amino group which may be substituted (forexample, amino, mono-C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, 5- to6-membered cycloamino such as tetrahydropyrrole, piperazine, piperidine,morpholine, thiomorpholine, pyrrole, imidazole, etc., or the like),carboxyl group which may be esterified or amidated (for example,carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl,di-C₁₋₄ alkylcarbamoyl, etc.), C₁₋₄ alkyl which may be halogenated (forexample, trifluoromethyl, methyl, ethyl, etc.), C₁₋₄ alkoxy which may behalogenated (for example, methoxy, ethoxy, trifluoromethoxy,trifluoroethoxy, etc.), formyl, C₂₋₄ alkanoyl (for example, acetyl,propionyl, etc.), C₁₋₄ alkylsulfonyl (for example, methanesulfonyl,ethanesulfonyl, etc.), and the like; and the number of the substituentsis preferably 1 to 3.

In the above formula (I), the counter anion for the case where thephosphorus atom forms a phosphonium salt, may be exemplified by, inaddition to anions of halogen (for example, Cl⁻, Br⁻, I⁻, etc.), anionsderived from inorganic acids such as hydrochloric acid, hydrobromicacid, nitric acid, sulfuric acid, phosphoric acid, etc.; anions derivedfrom organic acids such as formic acid, acetic acid, trifluoroaceticacid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citricacid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, etc.; and anions derived from acidic aminoacids such as aspartic acid, glutamic acid, etc., and among them, Cl⁻,Br⁻, I⁻ and the like are preferred.

The amino group which may be substituted represented by R⁹ and R¹⁰ maybe exemplified by an amino group which may have one or two of:

(1) alkyl which may be substituted (for example, C₁₋₁₀ alkyl such asmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl,decyl, etc., and preferably lower (C₁₋₆) alkyl, or the like);

(2) cycloalkyl which may be substituted (for example, C₃₋₇ cycloalkylsuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,etc., or the like);

(3) alkenyl which may be substituted (for example, alkenyl having 2 to10 carbon atoms, such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., andpreferably lower (C₂₋₆) alkenyl, or the like);

(4) cycloalkenyl which may be substituted (for example, cycloalkenylhaving 3 to 7 carbon atoms, such as 2-cyclopentenyl, 2-cyclohexenyl,2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc., or the like);

(5) formyl, or acyl which may be substituted (for example, alkanoylhaving 2 to 4 carbon atoms (for example, acetyl, propionyl, butyryl,isobutyryl, etc.), alkylsulfonyl having 1 to 4 carbon atoms (forexample, methanesulfonyl, ethanesulfonyl, etc.), or the like);

(6) aryl which may be substituted (for example, phenyl, naphthyl, etc.);or the like.

Examples of the substituent of the above-described (1) alkyl which maybe substituted, (2) cycloalkyl which may be substituted, (3) alkenylwhich may be substituted, (4) cycloalkenyl which may be substituted, (5)acyl which may be substituted, and (6) aryl which may be substituted,include halogen (for example, fluorine, chlorine, bromine, iodine,etc.), nitro, cyano, hydroxy group, thiol group which may be substituted(for example, thiol, C₁₋₄ alkylthio, etc.), amino group which may besubstituted (for example, amino, mono-C₁₋₄ alkylamino, di-C₁₋₄alkylamino, 5- to 6-membered cycloamino such as tetrahydropyrrole,piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole,etc.), carboxyl group which may be esterified or amidated (for example,carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl, mono-C₁₋₄ alkylcarbamoyl,di-C₁₋₄ alkylcarbamoyl, etc,), C₁₋₄ alkyl which may be halogenated (forexample, trifluoromethyl, methyl, ethyl, etc.); C₁₋₄ alkoxy which may behalogenated (for example, methoxy, ethoxy, trifluoromethoxy,trifluoroethoxy, etc.), formyl, C₂₋₄ alkanoyl (for example, acetyl,propionyl, etc.), C₁₋₄ alkylsulfonyl (for example, methanesulfonyl,ethanesulfonyl, etc.), and the like, and the number of the substituentsis preferably 1 to 3.

The substituent of the “amidino group which may be substituted” and the“guanidino group which may be substituted” represented by R², may beexemplified by the same one as the substituent of the above-described“amino which may be substituted, in which the nitrogen atom may beconverted to a quaternary ammonium or an oxide” represented by R^(2.)

R² is preferably (1) an amino group which may be substituted, in whichthe nitrogen atom may be converted to a quaternary ammonium or an oxide,(2) a nitrogen-containing heterocyclic group which may be substitutedand may contain a sulfur atom or an oxygen atom as the ring-constitutingatom, in which the nitrogen atom may be converted to a quaternaryammonium or an oxide, (3) an amidino group which may be substituted, or(4) a guanidino group which may be substituted. R² is more preferably anamino group which may be substituted, in which the nitrogen atom may beconverted to a quaternary ammonium; a nitrogen-containing heterocyclicgroup which may be substituted and may contain a sulfur atom or anoxygen atom as the ring-constituting atom, which may be converted to anoxide; or the like. In particular, it is preferably an amino group whichmay be substituted; a nitrogen-containing heterocyclic group which maybe substituted and may contain a sulfur atom or an oxygen atom as thering-constituting atom; or the like.

R² is more preferably a group represented by the formula —NRR″ or—N⁺RR′R″, wherein R, R′ and R″ are each an aliphatic hydrocarbon group(linear aliphatic hydrocarbon group and cyclic aliphatic hydrocarbongroup) which may be substituted, or an alicyclic (non-aromatic)heterocyclic group which may be substituted, or a nitrogen-containingaromatic heterocyclic group which may be substituted, in which thenitrogen atom may be converted to an oxide.

In the above formulas, the “aliphatic hydrocarbon group which may besubstituted” and the “alicyclic heterocyclic group which may besubstituted” represented by R, R′ and R″ may be exemplified by the sameone as the “aliphatic hydrocarbon group which may be substituted (forexample, alkyl, cycloalkyl, alkenyl, cycloalkenyl, etc., each of whichmay be substituted)” and the “alicyclic heterocyclic group which may besubstituted (for example, 5- or 6-membered non-aromatic heterocyclewhich may be substituted, etc.)” that are exemplified as the substituentwhich may be carried by the “amino which may be substituted” representedby substituent R^(2.)

Among them, R and R′ are each preferably a linear hydrocarbon groupwhich may be substituted (for example, alkyl, alkenyl, etc., each ofwhich may be substituted), more preferably a C₁₋₆ alkyl group which maybe substituted, and particularly preferably a methyl group which may besubstituted.

R″ is preferably an alicyclic hydrocarbon group which may be substituted(preferably, a C₃₋₈ cycloalkyl group which may be substituted; morepreferably, cyclohexyl which may be substituted) or an alicyclicheterocyclic group which may be substituted (preferably, a saturatedalicyclic heterocyclic group which may be substituted (preferably, a6-membered cyclic group); more preferably, tetrahydropyranyl which maybe substituted, tetrahydrothiopyranyl which may be substituted, orpiperidyl which may be substituted; particularly preferably,tetrahydropyranyl which may be substituted).

Furthermore, as the “nitrogen-containing aromatic heterocyclic group” ofthe “nitrogen-containing aromatic heterocyclic group which may besubstituted, in which the nitrogen atom may be converted to an oxide”represented by R², pyridine, imidazole, triazole and imidazopyridine areexemplified as preferred, and among these, imidazole and triazole areparticularly preferred.

The “amino group which may be substituted, in which the nitrogen atommay be converted to a quaternary ammonium or an oxide” represented by R²and R² or the like may be exemplified respectively by the same one asthe group corresponding to the above-described R^(2.)

The compound represented by formula (I) is preferably the compound ofthe following:

-   (Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(2-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide,    (Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-hydroxypyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide,    (Ss)-(2E)-3-[4-(3-(acetoxymethyl)pyrrolidin-1-yl)-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide,    (Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-(methoxycarbonyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide,    (Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-carbamoylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide,    (Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide,    (Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-(hydroxymethyl)pyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide,    (Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-carboxypyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide    and diastereomers thereof,-   (Ss)-(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-(3-methylpyrrolidin-1-yl)pyridin-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide,    (Ss)-(2E)-3-[2-[3-(acetoxymethyl)pyrrolidin-1-yl]-5-[4-(2-butoxyethoxy)phenyl]pyridin-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide,    (Ss)-(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-[3-(hydroxymethyl)pyrrolidin-1-yl)pyridin-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide    and diastereomers thereof,-   (S)-(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]but-2-enamide,    (S)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3,4-dimethylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide,    (S)-(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-pyrrolidin-1-ylpyridin-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide,    (S)-(2E)-3-[6-[4-(2-butoxyethoxy)phenyl]-1-methyl-1,2,3,4-tetrahydroquinolin-8-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide    and the like.

The salt of the compound represented by formula (I) of the presentinvention is preferably a pharmaceutically acceptable salt and may beexemplified by salts with inorganic bases, salts with organic bases,salts with inorganic acids, salts with organic acids, salts with basicor acidic amino acids, or the like. Preferred examples of the salt withinorganic base include alkali metal salts such as sodium salt, potassiumsalt, etc.; alkaline earth metal salts such as calcium salt, magnesiumsalt, etc.; aluminum salt, ammonium salt and the like. Preferredexamples of the salt with organic base include salts withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine,N,N′-dibenzylethylenediamine and the like. Preferred examples of thesalt with inorganic acid include salts with hydrochloric acid,hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and thelike. Preferred examples of the salt with organic acid include saltswith formic acid, acetic acid, trifluoroacetic acid, fumaric acid,oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid,malic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid and the like. Preferred examples of the salt withbasic amino acid include salts with arginine, lysine, ornithine and thelike. Preferred examples of the salt with acidic amino acid includesalts with aspartic acid, glutamic acid and the like. The compoundrepresented by formula (I) of the present invention may be eitherhydrate or anhydrate. When the compound represented by formula (I) ofthe present invention exists as configurational isomers, diastereomers,conformers or the like, each form can be isolated by the separation andpurification means that are known per se in the art, if desired.Further, when the compound represented by formula (I) is a racemate, the(S) and (R) isomers may be separated by general means for opticalresolution, and each of the optical isomers as well as the racemates isincluded in the scope of the present invention.

The prodrug of the compound represented by formula (I) used in theinvention or a salt thereof [hereinafter, may be sometimes referred toas Compound (I)] refers to a compound which is converted to Compound (I)by an in vivo reaction caused by an enzyme, gastric acid or the likeunder physiological conditions, that is, a compound which is convertedto Compound (I) upon occurrence of enzymatic oxidation, reduction,hydrolysis or the like, or a compound which is converted to Compound (I)upon occurrence of hydrolysis or the like by gastric acid or the like.The prodrug of Compound (I) may be exemplified by compounds resultingfrom acylation, alkylation or phosphorylation of the amino group ofCompound (I) (for example, the compounds in which the amino group ofCompound (I) is in the form of eicosanoyl, alanyl, pentylaminocarbonyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl,pyrrolidylmethyl, pivaloyloxymethyl, tert-butyl or the like); compoundsresulting from acylation, alkylation, phosphorylation or boration of thehydroxy group of Compound (I) (for example, the compounds in which thehydroxy group of Compound (I) is in the form of acetyl, palmitoyl,propanoyl, pivaloyl, succinyl, fumaryl, alanyl,dimethylaminomethylcarbonyl or the like); compounds resulting fromesterification or amidation of the carboxyl group of Compound (I) (forexample, the compounds in which the carboxyl group of Compound (I) is inthe form of ethyl ester, phenyl ester, carboxymethyl ester,dimethylaminomethyl ester, pivaloyloxymethyl ester,ethoxycarbonyloxyethyl ester, phthalidyl ester,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester,cyclohexyloxycarbonylethyl ester, methylamide or the like); or the like.These compounds can be prepared from Compound (I) by methods known perse in the art.

Furthermore, the prodrug of Compound (I) may be also a compound which isconverted to Compound (I) under physiological conditions, as describedin “Development of Pharmaceutical Products”, Vol. 7, Design ofMolecules, Hirokawa Publisher, pp. 163-198 (1990).

Also, Compound (I) may be labeled with isotopes (for example, ³H, ¹⁴C,³⁵S, ¹²⁵I, etc.).

Hereinafter, a process for producing the compound represented by formula(I) or a salt thereof will be explained.

The compound represented by formula (I) or a salt thereof can beproduced by those processes known per se. For example, it can beproduced by the following processes. In addition, the compound offormula (I) or a salt thereof can be produced by the process describedin JP-A No. 8-73476 or a similar method thereto.

The compounds which will be used in each of the following processes mayform salts similar to the salt of Compound (I), as far as the salts donot interfere with reactions.

Further, in the following reactions, when the starting compounds haveamino, carboxyl or hydroxy groups as substituents, these groups may beprotected by protective groups which are commonly used in peptidechemistry, and if necessary, the protective groups may be removed afterthe reactions to obtain desired compounds.

Examples of the protective group to be used for an amino group includeC₁₋₆ alkylcarbonyl which may be substituted (for example, acetyl,propionyl, etc), formyl, phenylcarbonyl, C₁₋₆ alkyloxycarbonyl (forexample, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.),phenyloxycarbonyl (for example, benzoxycarbonyl, etc.), C₇₋₁₀aralkyloxycarbonyl (for example, benzyloxycarbonyl, etc.), trityl,phthaloyl and the like. Examples of the substituent of the aboveprotective groups include halogen atom (for example, fluorine, chlorine,bromine, iodine, etc.), C₁₋₆ alkylcarbonyl (for example, acetyl,propionyl, butyryl, etc.), nitro group and the like, and the number ofthe substituents is about 1 to 3.

Examples of the protective group to be used for a carboxyl group includeC₁₋₆ alkyl which may be substituted (for example, methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl and the like.Examples of these substituents include halogen atom (for examplefluorine, chlorine, bromine, iodine, etc.), C₁₋₆ alkylcarbonyl (forexample, acetyl, propionyl, butyryl, etc.), formyl, nitro and the like,and the number of the substituents is about 1 to 3.

Examples of the protective group to be used for a hydroxy group includeC₁₋₆ alkyl which may be substituted (for example, methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, etc.), phenyl, C₇₋₁₀ aralkyl (for example,benzyl, etc.), C₁₋₆ alkylcarbonyl (for example, acetyl, propionyl,etc.), formyl, phenyloxycarbonyl, C₇₋₁₀ aralkyloxycarbonyl (for example,benzyloxycarbonyl, etc.), pyranyl, furanyl, silyl and the like. Thesubstituents of these protective groups include halogen atom (forexample, fluorine, chlorine, bromine, iodine, etc.), C₁₋₆ alkyl, phenyl,C₇₋₁₀ aralkyl, nitro and the like, and the number of the substituents isabout 1 to 4.

Introduction and removal of protective groups are carried out accordingto those methods known per se or similar methods thereto [for example,the method described in “Protective Groups in Organic Chemistry”, (J. F.W. McOmie et al., Plenum Press)], and removal is carried out by, forexample, the methods of treating with an acid, a base, a reducing agent,ultraviolet light, hydrazone, phenylhydrazine, sodiumN-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetateor the like.

In the following description, the compounds represented by formulas (I),(Ia), (Ib), (II) and (III) including their salts may be also simplyreferred to as Compound (I), Compound (Ia), Compound (Ib), Compound (II)and Compound (III).

[Process A]

Compound (I) can be prepared by reacting Compound (II) with Compound(III) according to the following reaction:

wherein each symbol has the same meaning as defined above.

In this reaction, a carboxylic acid derivative (II) is reacted with anamine derivative (III) to prepare Compound The condensation reaction ofCompound (II) and Compound (III) may be conducted by a conventionalmeans for peptide synthesis. The means for peptide synthesis may becarried out according to any method known in the art, for example, themethods described in M. Bodansky and M. A. Ondetti, Peptide Synthesis,Interscience, New York (1996); F. M. Finn and K. Hofmann, The Proteins,Vol. 2; H. Nenrath and R. L. Hill, Ed., Academic Press Inc., New York(1976); and Nobuo Izumiya et al., Foundation and Experiments in PeptideSynthesis, Maruzen (1985), which include, for example, azide method,chloride method, acid anhydride method, mixed acid anhydride method, DCCmethod, activated ester method, method using Woodward's Reagent K,carbonyldiimidazole method, oxidation/reduction method, DCC/HONB method,as well as WSC method, diethyl cyanophosphate (DEPC) method and thelike. In other words, examples of the reactive derivatives that may beused include acid halides (for example, acid chloride, acid bromide,etc.), acid azides, acid anhydrides, mixed acid anhydrides [for example,mixed acid anhydrides of mono-C₁₋₆ alkylcarbonic acid (for example,mixed acid anhydrides of a free acid with monomethylcarbonic acid,monoethylcarbonic acid, monoisopropylcarbonic acid, monoisobutylcarbonicacid, mono-tert-butylcarbonic acid, monobenzylcarbonic acid,mono(p-nitrobenzyl)carbonic acid, or monoallylcarbonic acid, etc.),mixed acid anhydrides of C₁₋₆ aliphatic carboxylic acid (for example,mixed acid anhydrides of a free acid with acetic acid, trichloroaceticacid, cyanoacetic acid, propionic acid, butyric acid, isobutyric acid,valeric acid, isovaleric acid, pivalic acid, trifluoroacetic acid,trichloroacetic acid, acetoacetic acid, etc.), mixed acid anhydrides ofC₇₋₁₂ aromatic carboxylic acid (for example, mixed acid anhydrides of afree acid with benzoic acid, p-toluic acid, p-chlorobenzoic acid, etc.),mixed acid anhydrides of organic sulfonic acid (for example, mixed acidanhydrides of a free acid with methanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid, etc.) etc.],activated amides, activated esters (for example, diethoxyphosphoric acidester, diphenoxyphosphoric acid ester, p-nitrophenyl ester,2,4-dinitrophenyl ester, etc.), activated thioesters (for example,2-pyridylthiol ester, 2-benzothiazolylthiol ester, etc.) and the like.This condensation reaction can be carried out in a solvent. Examples ofthe solvent include N,N-dimethylformamide, dimethylsulfoxide, pyridine,chloroform, dichloromethane, tetrahydrofuran, dioxane, acetonitrile,each of which is dehydrated or hydrated, or appropriate mixturesthereof. The reaction temperature is usually about −20° C. to about 50°C., and preferably about −10° C. to about 30° C. The reaction time isabout 1 to about 100 hours, and preferably about 2 to about 40 hours.The thus-obtained Compound (I-1) can be isolated and purified by knownseparation and purification means such as concentration, vacuumconcentration, solvent extraction, crystallization, recrystallization,resolubilization, chromatography or the like.

[Process B]

(1) When R^(2a′) as represented in Compound (I-2) is, for example, atertiary amine residue, Compound (I-2) can be reacted with an alkylhalide or an aralkyl halide to prepare a quaternized Compound (I′).Herein, examples of the halogen atom include chlorine, bromine, iodine,etc, and the alkyl halide (for example, a lower (C₁₋₆) alkyl halide,etc.), or the aralkyl halide (for example, a lower (C₁₋₄) alkylphenylhalide, etc.) is typically used in an amount of about 1 to 5 moles withrespect to 1 mole of Compound (I-2). The reaction may be carried out inan inert solvent, for example, toluene, benzene, xylene,dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide(DMF), dimethylacetamide, etc., or a mixture of the solvents above. Thereaction temperature is in a range of about 10° C. to about 160° C., andpreferably about 20° C. to about 120° C. The reaction time is about 1 toabout 100 hours, and preferably about 2 to about 40 hours. The reactionis preferably carried out under an inert gas atmosphere (for example,nitrogen, argon, etc.).

(2) When R^(2a′) as represented in Compound (I-2) is, for example, asecondary amine residue, Compound (I-2) can be reacted with an alkylhalide or an aralkyl halide to prepare a tertiarized Compound (I′).Herein, examples of the halogen atom include chlorine, bromine, iodine,etc., and the alkyl halide or aralkyl halide is typically used in anamount of about 1 to 2 moles with respect to 1 mole of Compound (I-2).The reaction can be facilitated, if necessary, by addition of about 1 toabout 3 moles of a base such as triethylamine, diisopropylethylamine,pyridine, lithium hydride, sodium hydride, sodium methoxide, sodiumethoxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate or the like, and by further adding sodium iodide, potassiumiodide, or the like.

This reaction of tertiary amination can be carried out in an inertsolvent such as methanol, ethanol, propanol, isopropanol, n-butanol,tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene,benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane,dimethylformamide (DMF), dimethylsulfoxide (DMSO), pyridine, etc., or amixture of the solvents above. The reaction is carried out at atemperature ranging from about 0° C. to about 180° C. for about 1 toabout 40 hours. Also, the reaction is preferably carried out under aninert gas atmosphere (for example, nitrogen, argon, etc.).

(3) When R^(2a′) as represented in Compound (I-2) is, for example, asecondary amine residue, Compound (I-2) can be reacted with an aldehydecompound in the presence of a reductive amino reagent such as sodiumtriacetoxyborohydride, sodium cyanoborohydride, sodium borohydride orthe like to prepare a tertiarized Compound (I′). The reaction conditionsfor this reductive amination reaction are preferably changed dependingon the reagent used. For example, when sodium triacetoxyborohydride isused, the reaction is preferably conducted in an inert solvent, forexample, dichloromethane, chloroform, 1,2-dichloroethane,tetrahydrofuran (THF), diethyl ether, dioxane, acetonitrile,dimethylformamide (DMF), etc., or a mixture of the solvents above. Thereagent is used in an amount of about 1 to 2 molar equivalents withrespect to 1 mole of Compound (I-2). The reaction is usually carried outat a temperature ranging from about 0° C. to about 80° C. for about 1 toabout 40 hours. The reaction is preferably carried out under an inertgas atmosphere (for example, nitrogen, argon, etc.).

(4) When R^(2a′) as represented in Compound (I-2) is, for example, asulfide residue or a tertiary amine residue, or when Z² is, for example,a sulfide residue, Compound (I-2) can be reacted with an oxidizingagent, for example, m-chloroperbenzoic acid, perbenzoic acid,p-nitroperbenzoic acid, magnesium monoperoxyphthalate, peracetic acid,hydrogen peroxide, sodium periodate, potassium periodate, etc., toprepare a Compound (I′) having a sulfinyl group, a sulfonyl group or anamine oxide group. The reaction conditions for this oxidation reactionare preferably changed in accordance with the oxidizing agent used. Forexample, when m-chloroperbenzoic acid is used, the reaction may becarried out in an inert solvent, for example, dichloromethane,chloroform, 1,2-dichloroethane, diethyl ether, tetrahydrofuran, acetone,ethyl acetate, etc., or a mixture of the solvents above. The oxidizingagent is used in an amount of about 1 to 3 molar equivalents withrespect to 1 mole of Compound (I-2). The reaction is usually carried outat a temperature ranging from about −78° C. to about 80° C. (preferablyfrom −50 to 25° C.), for about 1 to about 40 hours.

Alternatively, when Z² as represented in Compound (I-2) is, for example,a sulfide residue, a Compound (I′) having an optically active sulfinylgroup can be prepared according to methods that are known per se in theart, for example, the method described in Ojima, I., Ed., CatalyticAsymmetric Synthesis, 2000, Wiley-VCH (New York), or a similar methodthereto.

[Process C]

V of Compound (IV) represents a halogen atom (chlorine, bromine, iodine,etc.) or a sulfonyloxy group (methanesulfonyloxy group,trifluoromethanesulfonyloxy group, benzenesulfonyloxy group,toluenesulfonyloxy group, etc.), and the other symbols have the samemeanings as defined above.

(1) Compound (IV) can be reacted with a tertiary amine to prepare aquaternized Compound (I′). This reaction can be carried out in an inertsolvent, for example, toluene, benzene, xylene, dichloromethane,chloroform, 1,2-dichloroethane, dimethylformamide (DMF),dimethylacetamide, etc., or a mixture of the solvents above. Thetertiary amine is used in an amount of about 1 to 3 moles with respectto 1 mole of Compound (IV). The reaction is carried out at a temperatureranging from about 10° C. to about 120° C. for about 1 to about 40hours. The reaction is preferably carried out under an inert gasatmosphere (for example, nitrogen, argon, etc.).

(2) Compound (IV) can be reacted with a tertiary phosphine to prepare aquaternized Compound (I′). This reaction can be carried out in an inertsolvent, for example, toluene, benzene, xylene, dichloromethane,chloroform, 1,2-dichloroethane, acetonitrile, dimethylformamide (DMF),etc., or a mixture of the solvents above. The tertiary phosphine is usedin an amount of about 1 to 2 moles with respect to 1 mole of Compound(IV). The reaction is carried out at a temperature ranging from about20° C. to about 150° C. for about 1 to about 50 hours. The reaction ispreferably carried out under an inert gas atmosphere (for example,nitrogen, argon, etc.).

(3) Compound (IV) can be reacted with a primary or a secondary aminecompound or a thiol compound to prepare a Compound (I′) having asecondary or tertiary amino group or a thio group. The primary orsecondary amine compound or the thiol compound is usually used in anamount of about 1 to 3 moles with respect to 1 mole of Compound (IV).This reaction can be facilitated, if necessary, by adding about anequivalent to three-fold moles of a base such as triethylamine,diisopropylethylamine, pyridine, lithium hydride, sodium hydride, sodiummethoxide, sodium ethoxide, sodium carbonate, potassium carbonate,sodium hydrogen carbonate or the like, and by further adding sodiumiodide, potassium iodide or the like. The substitution reaction can becarried out in an inert solvent, for example, methanol, ethanol,propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether,dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane,chloroform, 1,2-dichloroethane, dimethylformamide (DMF),dimethylsulfoxide (DMSO), pyridine, etc., or a mixture of the solventsabove. The reaction is carried out at a temperature ranging from about−10° C. to about 180° C. for about 1 to about 40 hours. The reaction ispreferably carried out under an inert gas atmosphere (for example,nitrogen, argon, etc.).

[Process D]

(1) Compound (V), wherein V′ represents a halogen atom (bromine, iodine,etc.) or a sulfonyloxy group (trifluoromethanesulfonyloxy group, etc),and the other symbols have the same meanings as described above, can besubjected to, for example, the Suzuki reaction [a cross-condensationreaction of an arylboric acid and, for example, an aryl halide oraryloxytrifluoromethanesulfonate, catalyzed by a palladium catalyst; A.Suzuki et al., Synth. Commun., 11, 513 (1981)], to prepare a Compound(I″) in which X¹ is a bond, and R^(1′) is a 5- or 6-membered aromaticgroup. The aryl borate can be used in an amount of about an equivalentto 1.5-fold moles with respect to 1 mole of Compound (V) to giveCompound (I″).

Further, Compound (V) can be subjected to, for example, across-condensation reaction with an arylacetylene compound in thepresence of a palladium catalyst[dichlorobis(triphenylphosphine)palladium, etc.] [K. S. Y. Lau et al.,J. Org. Chem., 46, 2280 (1981); J. W. Tilley, S. Zawoisky et al., J,Org. Chem., 53, 386 (1988)] to give a Compound (I″) having an acetylenebond, in which X¹ represents —C≡C—. The arylacetylene compound can beused typically in an amount of about an equivalent to two-fold moleswith respect to 1 mole of Compound (V) to prepare Compound (I″).

(2) Compound (V), wherein V′ represents a hydroxy group, and the othersymbols have the same meanings as described above, can be subjected to,for example, the Mitsunobu reaction [an etherification reaction using,for example, triphenylphosphine and diethyl azodicarboxylate as thecondensing agents; O. Mitsunobu et al., Synthesis, 1 (1981)] to prepareCompound (I″) having an ether bond. The corresponding alcohol compoundor phenol compound can be used in an amount of about an equivalent tothree-fold moles with respect to 1 mole of Compound (V) to prepareCompound (I″).

The Compound (I″) having an ether bond can also be prepared by anetherification reaction of Compound (V) with a reactive compound such asa halide (chloride, bromide, iodide, etc.) compound, a tosylatecompound, a mesylate compound, etc. The reactive compound is usedtypically in an amount of about an equivalent to two-fold moles withrespect to 1 mole of Compound (V). This reaction can be facilitated, ifnecessary, by adding about an equivalent to three-fold moles of a basesuch as triethylamine, diisopropylethylamine, pyridine, lithium hydride,sodium hydride, sodium hydroxide, potassium hydroxide, sodium methoxide,sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, etc., and by further adding sodium iodide, potassium iodide,etc. The reaction may be carried out in an inert solvent such astetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene,benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane,dimethylformamide (DMF), dimethylsulfoxide (DMSO), pyridine, etc., or amixture of the solvents above. The reaction is carried out at atemperature ranging from about −10° C. to 180° C. for about 1 to about40 hours. The reaction is preferably carried out under an inert gasatmosphere (for example, nitrogen, argon, etc.).

(3) Compound (V), wherein V′ represents a carbonyl group which may besubstituted, a phosphonium salt or a phosphonic acid ester residue, andthe other symbols have the same meanings as defined above, can besubjected to, for example, the Wittig reaction [A. Maercker, Org.React., 14, 270 (1965)] or the Wittig-Horner-Emmons reaction [J. Boutagyand R. Thomas, Chem. Rev., 74, 87 (1974)] to prepare a Compound (I″)having a vinyl bond. The corresponding carbonyl compound, phosphoniumsalt or phosphonic acid ester compound is used in an amount of about anequivalent to 1.5-fold moles with respect to 1 mole of Compound (V).

[Process E]

(1) First, Compound (VI), wherein V″ represents a cyano group, and theother symbols have the same meanings as defined above, is reacted with alower alcohol such as methanol, ethanol, propanol, etc. in the presenceof an acid such as hydrochloric acid to give an imidate compound. Thisreaction is typically carried out using an excess of said alcohol, at atemperature ranging from about −10° C. to 50° C. for about 1 hour toabout 40 hours. The reaction can be conducted in an inert solvent suchas diethyl ether, 1,4-dioxane, toluene, benzene, xylene,dichloromethane, chloroform, 1,2-dichloroethane, etc., or a mixture ofthe solvents above.

Subsequently, the resulting imidate compound can be subjected to asubstitution reaction with a primary or secondary amine compound toprepare an amidine compound [I′″]. The primary or secondary aminecompound is used typically in an amount of about 1 to 5 moles withrespect to 1 mole of the imidate compound. The reaction can befacilitated, if necessary, by adding about an equivalent to three-foldmoles of a demineralizing agent such as triethylamine, pyridine, sodiumhydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide,sodium carbonate, potassium carbonate, etc. This substitution reactionmay be conducted in an inert solvent, for example, methanol, ethanol,propanol, isopropanol, n-butanol, tetrahydrofuran, diethyl ether,dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane,chloroform, 1,2-dichloroethane, dimethylformamide (DMF),dimethylsulfoxide (DMSO), pyridine, etc., or a mixture of the solventsabove. The reaction is carried out at a temperature ranging from about0° C. to 150° C. for about 1 to about 50 hours. The reaction is alsopreferably conducted under an inert gas (for example, nitrogen, argon,etc.) atmosphere.

(2) Compound (VI), wherein V″ is an amino group, and the other symbolshave the same meanings as defined above), can be subjected to asubstitution reaction with an S-alkyl (for example, methyl, ethyl,etc.)-isothiourea compound to give a guanidine Compound (I′″). TheS-alkyl-isothiourea compound is typically used in an amount of about anequivalent to two-fold moles with respect to 1 mole of Compound (VI).This reaction can be facilitated, if necessary, by adding about anequivalent to three-fold moles of a demineralizing agent such astriethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodiummethoxide, sodium ethoxide, sodium carbonate, potassium carbonate, etc.The substitution reaction may be carried out in an inert solvent, forexample, methanol, ethanol, propanol, isopropanol, n-butanol,tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, toluene,benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane,dimethylformamide (DMF), dimethylsulfoxide (DMSO), pyridine, etc., or amixture of the solvents above. The reaction is conducted at atemperature ranging from about 0° C. to 150° C. for about 1 to about 50hours. The reaction is also preferably carried out under an inert gasatmosphere (for example, nitrogen, argon, etc.).

The thus-obtained Compound (I) can be isolated and purified by knownseparation and purification means, for example, concentration, vacuumconcentration, solvent extraction, crystallization, recrystallization,resolubilization, chromatography and the like.

Compound (II-1) which is used as the starting material may be preparedby any known methods (for example, the methods described in JP-A No.11-263764; and JP-A No. 2001-026586, etc.) or similar methods thereto,for example, the method of reaction scheme I, methods in ReferenceExamples described below and modifications thereof.

wherein R¹¹ represents a C₁₋₄ alkyl group, X¹ and X² each represent aleaving group [halogen atom (chlorine, bromine, iodine, etc.),methanesulfonyloxy, trifluoromethanesulfonyl, benzenesulfonyloxy,toluenesulfonyloxy, etc.], and the other symbols have the same meaningsas defined above.

Compound (VII) can be subjected to a condensation reaction with an aminecompound in the presence of a base, to prepare Compound (VIII). Anunsaturated carboxylic acid ester (IX) can be prepared by subjectingCompound (VIII) to, for example, the Wittig reaction [A. Maercker, Org.React., 14, 270 (1965)] or the Wittig-Horner-Emmons reaction [J. Boutagyand R. Thomas, Chem. Rev., 74, 87 (1974)]. Compound (IX) can besubjected to, for example, the Suzuki reaction and subsequently to anester hydrolysis reaction, to prepare an unsaturated carboxylic acidCompound (II′).

Compound (II-1) which is used as the starting material can be preparedby any known methods (for example, the methods described in JP-A No.8-73476; and JP-A No. 2001-058988, etc.) or similar methods thereto, forexample, the method of reaction scheme I, methods in Reference Examplesdescribed below and modifications thereof.

Compound (III-1) also can be prepared by any known methods (for example,the method described in JP-A No. 8-73476, etc.) or similar methodsthereto, for example, the method of reaction scheme III, methods inReference Examples described below and modifications thereof.

wherein each symbol has the same meaning as defined above.

Reduction of Compound (XI) can be carried out by methods that are knownper se in the art. For example, reduction by metal, metal hydride ormetal hydrogen complex compound, reduction by diborane and substitutedborane, catalytic hydrogenation, or the like is used. That is, thisreaction is carried out by treating Compound (XI) with a reducing agent.Examples of the reducing agent include metals such as reduced iron, zincpowder, etc.; metal hydrogen complex compounds such as alkali metalborohydrides (for example, sodium borohydride, lithium borohydride,etc.), aluminum lithium hydride, etc.; metal hydrides such as sodiumhydride, etc.; organic tin compounds (triphenyltin hydride, etc.);metals and metal salts such as nickel compounds, zinc compounds, etc.;catalytic reducing agents using hydrogen and transition metal catalystssuch as palladium, platinum, rhodium, etc.; diborane; and the like. Thecatalytic reduction using hydrogen and a transition metal such aspalladium, platinum, rhodium, etc., and the reduction by a metal such asreduced iron are advantageously employed. The reaction is carried out inan organic solvent which does not interfere with the reaction. Thesolvent is appropriately selected for use from, for example, benzene,toluene, xylene, chloroform, carbon tetrachloride, dichloromethane,1,2-dichloroethane, 1,1,2,2-tetrachloroethane, diethyl ether,tetrahydrofuran, dioxane, methanol, ethanol, propanol, isopropanol,2-methoxyethanol, N,N-dimethylformamide, acetic acid or a mixture of thesolvents above, depending on the type of reducing agent. The reactiontemperature is about −20° C. to about 150° C., and particularlypreferably about 0° C. to about 100° C., while the reaction time isabout 1 to about 24 hours.

The thus-obtained Compound (III-1) can be isolated and purified by knownseparation and purification means such as concentration, vacuumconcentration, solvent extraction, crystallization, recrystallization,resolubilization, chromatography and the like.

The compound represented by formula (I) of the present invention or asalt thereof including the above-mentioned Compound (I-1), Compound(I-2), Compound (I′), Compound (I″) and Compound (I′″) (hereinafter,when it is said “the compound represented by formula (I)” in brief, itmeans to include a salt thereof and the compound represented by formula(I) and a salt thereof) can be administered orally or parenterally aloneor by as a pharmaceutical composition comprising the compound mixed witha pharmaceutically acceptable carrier in the form of a solid preparationsuch as tablet, capsule, granule, powder, etc., or a liquid preparationsuch as syrup, injectable solution, etc.

Examples of the dosage form for parenteral administration includeinjectable solution, infusion, suppository, vaginal suppository, etc.,and in particular, a vaginal suppository is useful for prevention of HIVinfection.

As the pharmaceutically acceptable carrier, a variety of organic orinorganic carriers that are commonly used as materials forpharmaceutical preparation may be used, and they are added as excipient,lubricant, binder and disintegrant in solid preparations, and assolvent, solubilizing agent, suspending agent, isotonic agent, buffer,soothing agent or the like in liquid preparations. Other additives forpreparation such as antiseptic agent, antioxidant, colorant, sweeteneror the like may also be used, if necessary. Preferred examples of theexcipient include lactose, sucrose, D-mannitol, starch, crystallinecellulose, light anhydrous silica and the like. Preferred examples ofthe lubricant include magnesium stearate, calcium stearate, talc,colloidal silica and the like. Preferred examples of the binder includecrystalline cellulose, sucrose, D-mannitol, dextrin,hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone and the like. Preferred examples of thedisintegrant include starch, carboxymethylcellulose, calciumcarboxymethylcellulose, sodium croscarmellose, sodiumcarboxymethylstarch and the like. Preferred examples of the solventinclude water for injection, alcohol, propylene glycol, macrogol, sesameoil, corn oil and the like. Preferred examples of the solubilizing agentinclude polyethylene glycol, propylene glycol, D-mannitol, benzylbenzoate, ethanol, trisaminomethane, cholesterol, triethanolamine,sodium carbonate, sodium citrate and the like. Preferred examples of thesuspending agent include surfactants such as stearyltriethanolamine,sodium laurylsulfate, laurylaminopropionic acid, lecithin, benzalkoniumchloride, benzethonium chloride, glycerin monostearate, etc.; andhydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone,sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose, etc.; and the like.Preferred examples of the isotonic agent include sodium chloride,glycerin, D-mannose and the like. Preferred examples of the bufferinclude buffer solutions of salts such as phosphate, acetate, carbonate,citrate and the like. Preferred examples of the soothing agent includebenzyl alcohol and the like. Preferred examples of the antiseptic agentinclude para-oxybenzoic acid esters, chlorobutanol, benzyl alcohol,phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.Preferred examples of the antioxidant include sulfite salts, ascorbicacid and the like.

The compound represented by formula (I) of the present invention or asalt thereof has excellent CCR antagonistic action, in particular, CCR5and/or CCR2 antagonistic action, and especially, a strong CCR5antagonistic action, and therefore may be used in prevention andtreatment of human HIV infection, for example, AIDS, and also inprevention and treatment of other various diseases. Further, thecompound represented by formula (I) of the present invention or a saltthereof has low toxicity and can be used safely.

For example, the pharmaceutical composition containing the compoundrepresented by formula (I) of the present invention or a salt thereofcan be used as a CCR5 antagonist, for example, a prophylactic and/ortherapeutic agent for AIDS and a suppressive agent for diseaseprogression of AIDS. Furthermore, the pharmaceutical compositioncontaining the compound represented by formula (I) of the presentinvention or a salt thereof may be used as a prophylactic and/ortherapeutic agent for a variety of diseases, such as a prophylacticand/or therapeutic agent for graft-versus-host diseases (GVHD) and/orrejection reaction, a prophylactic and/or therapeutic agent for chronicrheumatoid arthritis, autoimmune diseases, allergic diseases, ischemicbrain cell disorder, cardiac infarction, chronic nephritis andarteriosclerosis, and the like.

Examples of the diseases for which the prophylactic and/or therapeuticagent of the present invention is used, include graft rejection(posttransplantational rejection, posttransplantational polycythemia,hypertension, organ disorder, vascular hypertrophy, graft-versus-hostdiseases, etc.); arthritic osteopathic diseases such as periostitis,meningitis, etc. (chronic rheumatoid arthritis, osteoarthritisdeformans, rheumatoid myelitis, osteoporosis, abnormal growth of cell,fracture, refracture, osteomalacia, osseous Behcet's disease, rigorousmyelitis, articular tissue destruction by gonarthritis deformans anddiseases similar thereto, etc.); autoimmune diseases (collagen disease,SLE (systemic lupus erythematosus), pachyderma, polyarteritis,myasthenia gravis, multiple sclerosis, etc.); allergic diseases(allergic nasal catarrh, conjunctivitis, gastrointestinal allergy,pollinosis, anaphylaxis, atopic dermatitis, bronchial asthma, etc.);inflammatory enteropathic diseases (ulcerative colitis, Crohn's disease,gastritis, gastric ulcer, gastric cancer, postgastrotomic disorder,dyspepsia, esophageal ulcer, pancreatitis, polyp of the colon,cholelithiasis, hemorrhoids, peptic ulcer, situational ileitis, etc.);inflammatory diseases (retinopathy, postoperative and posttraumaticinflammation, remission of puffiness, pharyngitis, cystitis, meningitis,inflammatory ophthalmic diseases, etc.); respiratory diseases (coldsyndrome, pneumonia, asthma, pulmonary hypertension, pulmonarythrombi/pulmonary obliteration, pulmonary sarcoidosis, pulmonarytuberculosis, interstitial pneumonia, silicosis, adult tachypneasyndrome, chronic obliterative pulmonary diseases, etc.); infectiousdiseases (viral infection caused by cytomegalovirus, influenzavirus,herpesvirus and the like, Rickettsia infection, bacterial infection,sexually transmitted diseases, carinii pneumonia, Helicobacter pyloriinfection, systemic fungal infection, tuberculosis, invasiveStaphylococcal infection, acute viral encephalitis, acute bacterialmeningitis, AIDS encephalopathy, septicemia, sepsis, sepsis gravis,septic shock, endotoxin shock, toxic shock syndrome, etc.); cancers andaccompanying cachexia, cancer metastases (bladder cancer, breast cancer,cervical cancer, ovarian cancer, chronic lymphoblastic leukemia, chronicmyeloid leukemia, colon cancer, rectal cancer, colic cancer, multiplemyeloma, malignant myeloma, prostatic cancer, lung cancer, gastriccancer, Hodgkin's disease, malignant melanoma, malignant lymphoma,etc.); non-Hodgkin's lymphoma; non-small cell lung cancer; malignantmelanoma, neurodegenerative diseases (Alzheimer's disease, Parkinson'sdisease, amyotrophic lateral sclerosis (ALS), Huntington's chorea,diabetic neural disorder, Creutzfeldt-Jakob disease, etc.); mentaldiseases (depression, epilepsy, alcoholism etc.); schizophrenia; venousdysfunction; central nerve disorder (disorder andaftereffect/complication from intracerebral bleeding, brain infarctionand the like, cephalic trauma, spinal damage, brain edema, sensorymalfunction, sensory dysfunction, autonomic nervous malfunction,autonomic nervous dysfunction, etc.); central damage (cephalic trauma,spinal damage, whiplash injury, etc.); vascular dementia (multi-infarctdementia, Binswanger's disease, etc.); cerebrovascular accident(asymptomatic cerebrovascular accident, transient cerebral ischemicattack, stroke, cerebrovascular dementia, hypertensive encephalopathy,etc.); recurrence and aftereffect of cerebrovascular accident (neuralsymptoms, mental symptoms, subjective symptoms, operational disorder indaily life, etc.); cerebral vascular dementia; post-cerebrovascularobliteration central hypofunction; disorder or abnormality inautoregulation of cerebral circulation and renal circulation; bloodbrain barrier disorder; anxiety symptom; acute coronary artery syndromesincluding unstable angina, etc.; anxious mental state; amnesia;prosopalgia; otolaryngological diseases (Meniere's syndrome, tinnitus,gustation disorder, dizziness, dysequilibrium, dysphagia, etc.);migraine; chronic pain; dermatoses (keloid, angioma, psoriasis, etc.);arteriosclerosis obliterans; thromboangiitis obliterans; peripheralobstruction; postischemic reperfusion injury; Raynaud's disease;Buerger's disease; myocarditis; cardiac ischemia; cardiac infarction;progress of cardiac failure after cardiac infarction; cardiomyopathy;cardiac hypertrophy; acute cardiac failure and chronic (includingestatic) cardiac failure; angina pectoris; arrhythmia; tachycardia;circadian rhythm disorder of blood pressure; abnormality incharacteristic of blood haemocyte components (enhancement in plateletaggregation, abnormality of erythrocyte deformability, enhancement inleucocyte adhesiveness, increase in blood viscosity, polycythemia,vascular peliosis, autoimmune hemolytic anemia, disseminatedintravascular coagulation syndrome, multiple myelopathy, etc.);arteriosclerosis including atherosclerosis (aneurysm, coronaryarteriosclerosis, cerebral arteriosclerosis, peripheralarteriosclerosis, etc.); vascular reocclusion and restenosis afterbypass operation; vascular hyperplasia or occlusion and organmalfunction after intervention (transdermal coronary arterioplasty,stent detention, coronary autoscope, vascular ultrasound therapy,coronary injection thrombolytic therapy, etc.); production andenhancement of vasoactive materials and thrombi inducing materials(endothelin, thromboxane A2, etc.); arterialization (including abnormalvasculogenesis in abnormal capillary vasoganglion formation inatherosclerotic outer membrane); thrombosis; fat storage diseaseacceleration; ophthalmic diseases (glaucoma, ocular hypertension, etc.);hypertension; hypertensive tinnitus; dialysis hypotension; endothelialcell and organ disorders; endocrinopathy (Addison's disease, Cushing'ssyndrome, melanocytoma, primary aldosteronism, etc.); nephritis; renaldiseases (nephritis, glomerulonephritis, glomerulosclerosis, renalfailure, thrombotic microangiopathy, dialysis complications, organdisorders including nephropathy by radiation, diabetic nephropathy,etc.); diabetic diseases (insulin-dependent diabetes, diabeticcomplications, diabetic retinopathy, diabetic microangiopathy, diabeticneuropathy, etc.); glucose tolerance abnormality; hepatic diseases(hepatitis (including chronic hepatitis), hepatic cirrhosis, etc.);interstitial hepatic diseases; chronic pancreatitis; portal pressureenhancement; obesity; male sterility; gynecologic diseases (climactericdisorder, gestational toxicosis, endometriosis, hysteromyoma, ovariandiseases, mammary diseases, etc.); edema; chronic fatigue syndromes;prostatomegaly; Behcet's disease; Hodgkin's disease; lacunar infarction;consciousness disorder; psoriasis; diseases due to environmental oroccupational factors (disorder caused by radiation, disorders caused byultraviolet ray/infrared ray/laser ray, altitude sickness, etc.);intermittent claudication; and the like.

The pharmaceutical composition containing the compound represented byformula (I) or a salt thereof may vary depending on the kind of diseaseto be treated and may be used in combination with other drugs. Examplesof the other drugs include HDL-increasing drugs [squalene synthaseinhibitor, CETP inhibitor, LPL activator, etc.]; prophylactic and/ortherapeutic agents for HIV infection [nucleic acid reverse transcriptaseinhibitors such as zidovudine, didanosine, zalcitabine, lamivudine,stavudine, abacavir, adefovir, adefovir dipivoxil, fozivudine tidoxil,etc., non-nucleic acid reverse transcriptase inhibitors such asnevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, etc.,protease inhibitors such as saquinavir, ritonavir, indinavir,nelfinavir, amprenavir, palinavir, lasinavir, lopinavir, etc.]; NMG-COAreductase inhibitors [cerivastatin, atorvastatin, pravastatin,simvastatin, itavastatin, lovastatin, fluvastatin,(+)-3R,5S-7-[4-[4-fluorophenyl]-6-isopropyl-2-(N-methyl-N-methanesulfonylamino]pyrimidin-5-yl]-3,5-dihydroxy-6(E)-heptenoicacid, etc.]; atopic dermatitis drugs [sodium cromoglycate, etc.];allergic nasal catarrh drugs [sodium cromoglycate, chlorpheniraminemaleate, alimemazine tartrate, clemastine fumarate, homochlorcyclizinehydrochloride, terfenadine, mequitazine, etc.]; imipenem-cilastatinsodium; endotoxin antagonists or antibodies; oxidosqualene-lanosterolcyclases [e.g., decalin derivatives, azadecalin derivatives and indanederivatives]; calcium antagonists (diltiazem, etc.); glycerol;cholinesterase inhibitors (e.g., Aricept (donepezil), etc.); compoundssuppressing cholesterol uptake [e.g., sitosterol, neomycin, etc.];compounds inhibiting cholesterol biosyntheses [e.g., HMG-COA reductaseinhibitors such as lovastatin, simvastatin, pravastatin, etc.];

cyclooxygenase inhibitors [Cox-I, Cox-II inhibitors such as celecoxib,rofecoxib, salicylic acid derivatives such as aspirin and the like,diclofenac, indometacin, loxoprofen, etc.]; signal transductioninhibitors, squalene epoxidase inhibitors [e.g., NB-598 and theanalogous compounds, etc.]; steroidal drugs [dexamethasone, hexestrol,methimazole, betamethasone, triamcinolone, triamcinolone acetonide,fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone,cortisone acetate, hydrocortisone, fluorometholone, beclomethasonepropionate, estriol, etc.]; diacerin; nicotinic acid and derivatives andanalogues thereof [e.g., acipimox and probucol]; nicergoline, nephroticsyndrome drugs: prednisolone (Predonine), prednisolone sodium succinate(Predonine), methylprednisolone sodium succinate (Solumedrol),betamethasone (Rinderon), dipyridamole (Persantine), dilazephydrochloride (Comelian), ticlopidine, clopidogrel, antiplatelet drugsand anticoagulants such as FXa inhibitors, etc.; barpital-basedanticonvulsants or anaesthetic drugs (phenobarbital, mephobarbital,metharbital, etc.); Parkinson's disease drugs (e.g., L-DOPA, etc.);histamine receptor blockers (cimetidine, famotidine, etc.);hydantoin-based anticonvulsant drugs (phenyloin, mephenyloin, ethotoin,etc.); piroxicam, fibrates [e.g., clofibrate, benzafibrate, gemfibrozil,etc.]; prostaglandins; megestrol acetate; gastric and intraduodenalulcer drugs: antacids [e.g., histamine H2 antagonists (cimetidine,etc.), proton pump inhibitors (lansoprazole, etc.), etc.]; inflammatorymediator inhibitors; coronary vasodilators: nifedipine, diltiazem,nicoradil, nitrite drugs, etc.; infectious disease drugs: [e.g.,antibiotic formulations (cefotiam hydrochloride, cefozopranhydrochloride, ampicillin, etc.), chemotherapeutic agents (sulfa drugs,synthetic antibacterial agents, antiviral agents, etc.), biologicalformulations (vaccines, blood preparations including immunoglobulins)etc.] etc.; hepatic disease drugs: glycyrrhizin formulations [e.g.,Stronger Minophagen, etc.]; liver hydrolysate; SH compounds [e.g.,glutathione, etc.]; special amino acid formulations [e.g., aminoleban,etc.]; phospholipids [e.g., polyene-phosphatidylcholine, etc.];vitamins. [e.g., vitamin B₁, B₂, B₆, B₁₂, C, etc.]; adrenocorticalhormones [e.g., dexamethasone, betamethasone, etc.]; interferons [e.g.,interferon α, β, etc.]; hepatic encephalopathy drugs [e.g., lactulose,etc.];

hemostatic agents used in cases of rupture of esophageal and gastricvarices [e.g., vasopressin, somatostatin, etc.] etc.; arthritis drugs;muscle relaxants [pridinol, tubocurarine, pancuronium, tolperisonehydrochloride, chlorphenesin carbamate, baclofen, chlormezanone,mephenesin, chlorzoxazone, eperisone, tizanidine, etc.]; vasodilators[oxyfedrine, diltiazem, tolazoline, hexobendine, bamethan, clonidine,methyldopa, guanabenz, etc.]; vasoconstrictors [dopamine, dobutamine,denopamine, etc.]; platelet coagulation inhibitors (ozagrel, etc.);thrombogenesis prophylactic and/or therapeutic drugs: anticoagulantdrugs [e.g., heparin sodium, heparin calcium, warfarin calcium(Warfarin), Xa inhibitor]; thrombolytic drugs [e.g., tPA, urokinase];antiplatelet drugs [e.g., aspirin, sulfinpyrazone (Anturan),dipyridamole (Persantine), ticlopidine (Panaldine), cilostazol (Pletal),GPIIb/IIIa antagonists (ReoPro)]; antidepressants [imipramine,clomipramine, noxiptiline, fenelzin, amitriptyline hydrochloride,nortriptyline hydrochloride, amoxapine, mianserin hydrochloride,maprotiline hydrochloride, sulpiride, fluvoxamine maleate, trazodonehydrochloride, etc.]; antiepileptic drugs [gabapentin, phenyloin,ethosuximide, acetazolamide, chlordiazepoxide, trimethadione,carbamazepine, phenobarbital, primidone, sultiame, sodium valproate,clonazepam, diazepam, nitrazepam, etc.]; antiallergic drugs[diphenhydramine, chlorpheniramine, tripelennamine, methodilamine,clemizole, diphenylpyraline, methoxyphenamine, sodium cromoglycate,tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine,mequitazine, azalastine, epinastine, ozagrel hydrochloride, pranlukasthydrate, seratrodast, fexofenadine, ebastine, bucillamine, oxatomide,Stronger Neo-Minophagen C, tranexamic acid, ketotifen fumarate, etc.];anticholinergic drugs (e.g., ipratropium bromide, flutropium bromide,oxitropium bromide, etc.); anti-Parkinson drugs (dopamine, levodopa,etc.); antirheumatic drugs; anti-inflammatory drugs (e.g., aspirin,acetaminophen, diclofenac sodium, ibuprofen, indometacin, loxoprofensodium, dexamethasone, etc.); anticoagulant and antiplatelet drugs[sodium citrate, activated protein C, tissue factor pathway inhibitors,antithrombin III, dalteparin sodium, argatroban, gabexate, ozagrelsodium, ethyl icosapentate, beraprost sodium, alprostadil,pentoxifylline, tisokinase, streptokinase, hebarin, etc.]; anticoagulanttherapeutic drugs [dipyridamole (Bersantine), dilazep hydrochloride(Comelian), ticlopidine, clopidogrel, Xa inhibitors]; antibacterialdrugs [(1) sulfa drugs [sulfamethizole, sulfisoxazole,sulfamonomethoxine, sulfamethizole, salazosulfapyridine, sulfadiazinesilver, etc.], (2) quinoline-based antibacterial drugs [nalidixic acid,pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin,tosufloxacin tosilate, ciprofloxacin hydrochloride, lomefloxacinhydrochloride, sparfloxacin, fleroxacin, etc.], (3) antituberculousdrugs [isoniazid, ethambutol (ethambutol hydrochloride),p-aminosalicylic acid (calcium p-aminosalicylate), pyrazinamide,ethionamide, prothionamide, rifampicin, streptomycin sulfate, kanamycinsulfate, cycloserine, etc.], (4) anti-acid fast bacterial drugs[diaphenylsulfone, rifampicilin, etc.], (5) antiviral drugs[idoxuridine, acyclovir, vidarabine, ganciclovir, etc.], (6) anti-HIVdrugs [zidovudine, didanosine, zalcitabine, indinavir sulfateethanolate, ritonavir, etc.], (7) spirocheticide, (8) antibiotics[tetracycline hydrochloride, ampicillin, piperacillin, gentamicin,dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin,sisomicin, tetracycline, oxytetracycline, rolitetracycline, doxycycline,ampicillin, piperacillin, ticarcillin, cephalothin, cephapirin,cephaloridine, cefaclor, cephalexin, cefroxadine, cefadroxil,cefamandole, cefotiam, cefuroxime, cefotiam, cefotiam hexetil,cefuroxime axetil, cefdinir, cefditoren pivoxil, ceftazidime,cefpiramide, cefsulodin, cefinenoxime, cefpodoxime proxetil, cefpirome,cefozopran, cefepime, cefsulodin, cefinetazole, cefminox, cefoxitin,cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime, cefoperazone,ceftizoxime, moxalactam, thienamycin, sulfazecin, aztreonam or saltsthereof, griseofulvin, lankacidins [J. Antibiotics, 38, 877-885 (1985)],etc.],

cefixime, levofloxacin]; antithrombotic drugs (argatroban, etc.);antiprotozoal drugs [metronidazole, tinidazole, diethylcarbamazinecitrate, quinine hydrochloride, quinine sulfate, etc.]; antitumor drugs[6-O-(N-chloroacetylcarbamoyl]fumagillol, bleomycin, methotrexate,actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin,cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil,picibanil, lentinan, levamisole, bestatin, azimexon, glycyrrhizin,doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycinhydrochloride, peplomycin sulfate, vincristine sulfate, vinblastinesulfate, irinotecan hydrochloride, cyclophosphamide, melphalan,busulfan, thiotepa, procarbazine hydrochloride, cisplatin, azathioprine,mercaptopurine, tegafur, carmofur, cytarabine, methyltestosterone,testosterone propionate, testosterone enanthate, mepitiostane,fosfestrol, chlormadinone acetate, leuproline acetate, buserelinacetate, etc.]; antifungal drugs [(1) polyethylene-based antibiotics(e.g., amphotericin B, nystatin, trichomycin), (2) griseofulvin,pyrrolnitrin, etc., (3) cytosine metabolism antagonists (e.g.,flucytosine), (4) imidazole derivatives (e.g., econazole, clotrimazole,miconazole nitrate, bifonazole, croconazole), (5) triazole derivatives(e.g., fluconazole, itoraconazole, azole compounds[2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl-3-(2H,4H)-1,2,4-triazolone],(6) thiocarbamate derivatives [e.g., trinaphthol], (7)echinocandin-based derivatives (e.g., caspofungin, FK-463,V-echinocandin), etc.]; antipsychotic drugs [chlorpromazinehydrochloride, prochlorperazine, trifluoperazine, thioridazinehydrochloride, perphenazine maleate, fluphenazine enanthate,prochlorperazine maleate, levomepromazine maleate, promethazinehydrochloride, haloperidol, bromperidol, spiperone, reserpine,clocapramine hydrochloride, sulpiride, zotepine, etc.];

antiulcer drugs [metoclopramide, histidine hydrochloride, lansoprazole,metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine,urogastron, oxethazaine, proglumide, omeprazole, sucralfate, sulpiride,cetraxate, gefarnate, aldioxa, teprenone, prostaglandins, etc.];anti-diabetic drugs [e.g., pioglitazone, nateglinide, voglibose,acarbose, etc.]; antiobesity drugs (mazindol, etc.); antirheumaticdrugs, etc.; antianxiety drugs [diazepam, lorazepam, oxazepam,chlordiazepoxide, medazepam, oxazolam, cloxazolam, clotiazepam,bromazepam, etizolam, fludiazepam, hydroxyzine, etc.]; antiarrhythmicdrugs: disopyramide, lidocaine, quinidine sulfate, flecainide acetate,mexiletine hydrochloride, amiodarone hydrochloride, and β blockers, Caantagonists, etc.; antiasthmatic drugs [isoprenaline hydrochloride,salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate,trimetoxynol hydrochloride, tulobuterol hydrochloride, orciprenalinesulfate, fenoterol hydrobromide, ephedrine hydrochloride, ipratropiumbromide, oxitropium bromide, flutropium bromide, theophylline,aminophylline, sodium cromoglycate, tranilast, repirinast, amlexanox,ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine,ozagrel hydrochloride, pranlukast hydrate, seratrodast, dexamethasone,prednisolone, hydrocortisone, beclomethasone propionate, fluticasonepropionate, beclomethasone propionate, procaterol, etc.];anti-hypothyroidism drugs [dried thyroid (Thyreoid), levothyroxinesodium (Thyradin S), liothyronine sodium (thyronine, tyronamine)];nephrotic syndrome drugs [prednisolone (Predonine), prednisolone sodiumsuccinate (Predonine), methylprednisolone sodium succinate (Solumedrol),betamethasone (Rinderon)]; antihypertensive drugs [(1) sympathetic nerveinhibitors [α2 stimulants (e.g., clonidine, guanabenz, guanfacine,methyldopa, etc.), ganglionic blockers (e.g., hexamethonium,trimethaphan, etc.), presynaptic blockers (e.g., ArsA-Oxylone,dimethylaminoreserpinate, rescinnamine, reserpine, syrosingopine, etc.),neuronal blockers (e.g., betanidine guanethidine, etc.), α1 blockers(e.g., bunazosin, doxazosin, prazosin, terazosin, urapidil, etc.),

β blockers (e.g., propranolol, nadolol, timolol, nipradilol, bunitrolol,indenolol, penbutolol, carteolol, carvedilol, pindolol, acebutolol,atenolol, pisoprolol, metoprolol, labetalol, amosulalol, arotinolol,etc.), etc.], (2) vasodilators [calcium channel antagonists (e.g.,manidipine, nicardipine, nilvadipine, nisoldipine, nitrendipine,benidipine, amlodipine, aranidipine, etc.), phthalazine derivatives(e.g., budralazine, cadralazine, ecarazine, hydralazine, todralazine,etc.), etc.], (3) ACE inhibitors [alacepril, captopril, cilazapril,delapril, enalapril, lisinopril, temocapril, trandolapril, quinapril,imidapril, benazepril, perindopril, etc.)], (4) AII antagonists[losartan, candesartan, valsartan, telmisartan, irbesartan, forasartan,etc.], (5) diuretic drugs [e.g., diuretic drugs described above, etc.];antihypertensive drugs: diuretic drugs [e.g., furosemide (Lasix),bumetanide (Lunetoron), azosemide (Diart)], antihypertensive drugs[e.g., ACE inhibitors, (enalapril maleate (Renivace), etc.) and Caantagonists (manidipine, amlodipine, etc.), α or β receptor blockers,etc.], antihyperlipemia drugs [HMG-COA reductase inhibitors (e.g.,fluvastatin, cerivastatin, atorvastatin, etc.), fibrates [e.g.,simfibrate, aluminum clofibrate, clinofibrate, fenofibrate, etc.], anionexchange resins (e.g., cholestyramine, etc.), nicotinic acid drugs(e.g., nicomol, niceritrol, tocopherol nicotinate etc.), polyvalentunsaturated fatty acid derivatives (e.g., ethyl icosapentate, polyenephosphatidylcholine, melinamide, etc.), phytosterols (e.g.,gamma-oryzanol, soy sterol, etc.), elastase, sodium dextran sulfate,squalene synthase inhibitors, CETP inhibitors, ethyl2-chloro-3[4-(2-methyl-2-phenylpropoxy)phenyl]propionate [Chem. Pharm.Bull., 38, 2792-2796 (1990)], etc.]; osteopathic disease drugs: calciumformulations (e.g., calcium carbonate, etc.), calcitonin formulations,activated vitamin D₃ formulations (e.g., alfacalcidol (Alfarol, etc.),calcitriol (Rocaltrol), etc.),

sex hormones (e.g., estrogen, estrandiol, etc.), hormone formulations[e.g., conjugated estrogen (Premarin), etc.], ibriflavone formulations[Osten, etc.], vitamin K₂ vitamin K₂ formulations [e.g., menatetrenone(Glakay), etc.], bisphosphonate-based formulations (etidronate, etc.),prostaglandin E2, fluorine compounds (e.g., sodium fluoride, 1.5 etc.),bone morphogenetic protein (BMP), fibroblast growth factor (FGF),platelet derived growth factor (PDGF), transforming growth factor(TGF-β), insulin-like growth factor-1 and -2 (IGF-1,-2), parathyroidadrenal hormones (PTH), and compounds described in EP-A1-376197,EP-A1-460488, and EP-A1-719782 (e.g.,(2R,4S)-(−)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide,etc.), etc., fat-soluble vitamin drugs [(1) vitamin A family: vitaminA₁, vitamin A₂, and retinol palmitate, (2) vitamin D family: vitamin D₁,D₂, D₃, D₄ and D₅, (3) vitamin E family: α-tocopherol, β-tocopherol,γ-tocopherol, δ-tocopherol, dl-α-tocopherol nicotinate, (4) vitamin Kfamily: vitamin K₁, K₂, K₃ and K₄, (5) folic acids (vitamin M, etc.);vitamin derivatives [various vitamin derivatives, e.g., vitamin D₃derivatives such as 5,6-trans-cholecalciferol,2,5-hydroxycholecalciferol, 1-α-hydroxycholecalciferol, vitamin D₂derivatives such as 5,6-trans-ergocalciferol, and the like];disease-modifying antirheumatic and immunosuppressive drugs [e.g.,methotrexate, leflunomide, prograf, sulfasalazine, D-penicillamine, oralgold drugs]; hypertensors [dopamine, dobutamine, denopamine, digitoxin,digoxin, methyldigoxin, lanatoside C, G-strophanthin, etc.]; myocardialprotective drugs: heart ATP-K opener, Na—H exchange inhibitors,endothelin antagonists, urotensin antagonist, etc., cardiac failuredrugs [cardiac stimulants (e.g., digitoxin, digoxin, methyldigoxin,lanatoside C, proscillaridin, etc.), α, β stimulants (e.g., epinephrine,norepinephrine, isoproterenol, dopamine, docarpamine, dobutamine,denopamine, etc.), phosphodiesterase inhibitors (e.g., amrinone,milrinone, olprinone hydrochloride, etc.), calcium channel sensitivityenhancers (e.g., pimobentan, etc.), nitrate drugs (e.g., nitroglycerin,isosorbide nitrate, etc.), ACE inhibitors (e.g., the ACE inhibitordescribed above, etc.), diuretic drugs (e.g., diuretic drugs describedabove, etc.), calperitide, ubidecarenone, vesnarinone, aminophylline,etc.]; neurotrophic factors; renal failure and nephropathy drugs;biological formulations [e.g., monoclonal antibodies (e.g., anti-TNF-αantibodies, anti-IL-12 antibodies, anti-IL-6 antibodies, anti-ICAM-1antibodies, anti-CD4 antibodies, etc.), soluble receptors (e.g., solubleTNF-α receptors, etc.), protein ligands (IL-1 receptor antagonist,etc.)]; bile acid binding resins [e.g., cholestyramine, cholestipol,etc.]; biliary tract disease drugs: cholepoietic drugs [e.g.,dehydrocholic acid, etc.], cholekinetic drugs [e.g., magnesium sulfate,etc.], etc.; central nervous system agonists: antianxiety drugs,hypnotic and sedative drugs, anesthetic drugs, spasmolytic drugs,autonomic drugs, anti-Parkinson drugs and other psychoneuro drugs, etc.;antitussive and expectorants [ephedrine hydrochloride, noscapinehydrochloride, codeine phosphate, dihydrocodeine phosphate,isoproterenol hydrochloride, ephedrine hydrochloride, methylephedrinehydrochloride, alloclamide, clofedanol, picoperidamine, cloperastine,protokylol, isoproterenol, salbutamol, terbutaline, oxymetebanol,morphine hydrochloride, dextromethorphan hydrobromide, oxycodonehydrochloride, dimemorfan phosphate, tipepidine hibenzate, pentoxyverinecitrate, clofedanol hydrochloride, benzonatate, guaifenesin, bromhexinehydrochloride, ambroxol hydrochloride, acetylcysteine, ethylcysteinehydrochloride, carbocisteine, etc.], sedative drugs [chlorpromazinehydrochloride, atropine sulfate, phenobarbital, barbital, amobarbital,pentobarbital, thiopental sodium, thiamylal sodium, nitrazepam,estazolam, flurazepam, haloxazolam, triazolam, flunitrazepam,bromovalerylurea, chloral hydrate, triclofos sodium, etc.], analgesicand antiphlogistic drugs [e.g., central analgesic drugs. (e.g.,morphine, codeine, pentazocine etc.), steroidal drugs (e.g.,prednisolone, dexamethasone, betamethasone, etc.), antiphlogisticenzymic drugs (e.g., bromelain, lysozymes, proctase, etc.)], diabeticdrugs [sulfonylurea drugs (e.g., tolbutamide, chlorpropamide,glyclopyramide, acetohexamide, tolazamide, glibenclamide, glibuzole,etc.), biguanide drugs (e.g., metformin hydrochloride, buforminhydrochloride, etc.),

α-glucosidase inhibitors (e.g., voglibose, acarbose, etc.), insulinresistance improvers (e.g., pioglitazone, troglitazone, etc.), insulin,glucagon, diabetic complication drugs (e.g., epalrestat, thioctic acid,etc.), Actos, rosiglitazone, Kinedak, penfill, humulin, euglucon,glimicron, daonil, novolin, monotard, insulin family, glucobay, dimelin,rastinone, bacilcon, deamelin S, Iszilin acid, etc.]; brain functionactivating agents (e.g., idebenone, vinpocetine, etc.); urinary and malegenital disease drugs [e.g., prostatomegaly drugs (tamsulosinhydrochloride, prazosin hydrochloride, chlormadinone acetate, etc.),prostate cancer drugs (leuprorelin acetate, goserelin acetate,chlormadinone acetate, etc.)], etc; nonsteroidal antiinflammatory drugs[acetaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine,migrenin, aspirin, mefenamic acid, fulfenamic acid, diclofenac sodium,loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen,naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine,epirizole, tiaramide hydrochloride, zaltoprofen, gabexate mesilate,camostat mesilate, urinastatin, colchicine, probenecid, sulfinpyrazone,benzbromarone, allopurinol, sodium aurothiomalate, sodium hyaluronate,sodium salicylate, morphine hydrochloride, salicylic acid, atropine,scopolamine, morphine, pethidine, levorphanol, ketoprofen, naproxen,oxymorphone or salts thereof, etc.]; frequent urination and incontinencedrugs [flavoxate hydrochloride, etc.]; unstable plaque stabilizers [MMPinhibitors, chymase inhibitors, etc.]; arrhythmic drugs [sodium channelblockers (e.g., quinidine, procainamide, disopyramide, ajmaline,cibenzoline, lidocaine, diphenylhydantoin, mexiletine, propafenone,flecainide, pilsicainide, phenyloin, etc.), β blockers (e.g.,propranolol, alprenolol, bufetolol, oxprenolol, atenolol, acebutolol,metoprolol, pisoprolol, pindolol, carteolol, arotinolol, etc.),potassium channel blockers (e.g., amiodarone, etc.), calcium channelblockers (e.g., verapamil, diltiazem, etc.), etc.];

gynecologic disease drugs [e.g., climacteric disorder drugs (conjugatedestrogen, estradiol, testosterone enanthate, estradiol valerate, etc.),breast cancer drugs (tamoxifen citrate, etc.), endometriosis andhysteromyoma drugs (leuprorelin acetate, danazol, etc.)], etc.;anesthetic drugs [a. local anaesthetic drugs [cocaine hydrochloride,procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracainehydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride,oxybuprocaine hydrochloride, ethyl aminobenzoate, oxethazaine], etc.];b. systemic anesthetic drugs [(1) inhalation anesthetic drugs (e.g.,ether, halothane, nitrous oxide, influrane, enflurane), (2) intravenousanesthetic drugs (e.g., ketamine hydrochloride, droperidol, thiopentalsodium, thiamylal sodium, pentobarbital), etc.]]; anesthetic antagonists[levallorphan, nalorphine, naloxone, or salts thereof, etc.]; chroniccardiac failure drugs: cardiac stimulants [e.g., cardiac glycoside(digoxin), etc., β receptor stimulants (catecholamine preparations suchas denopamine, dobutamine), PDE inhibitors, etc.]; diuretic drugs [e.g.,furosemide (Lasix), spironolactone (Aldactone), bumetanide (Lunetoron),azosemide (Diart), etc.]; ACE inhibitors [e.g., enalapril maleate(Renivace), etc.]; Ca antagonists [e.g., amlodipine, manidipine, etc.]and β receptor blockers, etc.; immunomodulators [cyclosporin,tacrolimus, gusperimus, azathioprine, antilymphocyte sera, driedsulfonated immunoglobulins, erythropoietins, growth promotingglycoproteins, interleukins, interferons, etc.]; diuretic drugs[thiazide-based diuretic drugs (benzylhydrochlorothiazide,cyclopenthiazide, ethiazide, hydrochlorothiazide, hydroflumethiazide,methyclothiazide, penfluthiazide, polythiazide, trichlormethiazide,etc.), loop diuretic drugs (chlortalidone, clofenamide, indapamide,mefruside, meticrane, sotrazone, tribamide, quinethazone, metolazone,furosemide, mefruside, etc.), potassium-sparing diuretic drugs(spironolactone, triamterene, etc.)]; erectile dysfunction drugs(Viagra, apomorphine, etc.); and the like.

These drugs may be formulated, separately or simultaneously, by mixingwith pharmaceutically acceptable carriers, excipients, binders, diluentsor the like, and can be administered either orally or parenterally. Whenthe drugs are formulated separately, the separately preparedformulations may be mixed using a diluent or the like at the time of useand then administered, or each of the separately prepared formulationsmay be administered, simultaneously or separately with a time interval,to the same subject. Kit products that are to be used for mixing theseparately prepared formulations using a diluent or the like at the timeof use and administering (for example, an injection kit includingampoules for containing individual powdery drug, and a diluent formixing and dissolving two or more drugs at the time of use, and thelike), kit products that are to be used for administering each of theseparately prepared formulations, simultaneously or separately with atime interval, to the same subject (for example, a tablet kit foradministering two or more tablets, simultaneously or separately with atime interval, each tablet containing each of the drugs and placed inthe same or separate bags, with space for memorandum provided, ifnecessary, on the bags for indication of the drug administration time,or the like), and the like are also included to the pharmaceuticalcomposition of the present invention.

Dosage of the pharmaceutical composition of the present invention can beappropriately selected by taking into consideration of the subject to beadministered, age and body weight of the subject, symptoms,administration time, method of administration, dosage form and the like.

The dosage of a particular subject can be determined according to thesubject's age, body weight, general health condition, gender, meal,administration time, method of administration, excretion rate and theextent of disease condition of the patient at the time of treatment, bytaking into consideration of these and other factors.

When the pharmaceutical composition described above is used as aprophylactic and therapeutic agent for AIDS and as a suppressive agentfor disease progression of AIDS, the dosage may vary depending on thepatient's condition, body weight or the method of administration.However, in the case of oral administration, the daily dosage is in arange of about 5 to 1000 mg, preferably about 10 to 600 mg, morepreferably about 10 to 300 mg, and particularly preferably about 15 to150 mg, as the active ingredient [i.e. as the compound of formula (I)],for an adult having a body weight of 50 kg, and the composition isadministered once, or in 2 or 3 divided doses a day.

When the pharmaceutical composition described above is used as aprophylactic and therapeutic agent for graft-versus-host diseases and/orrejection associated with transplantation of organ such as heart,kidney, liver, bone marrow or the like, administration of thecomposition starts three days before the transplantation and iscontinued even after the transplantation. The daily dosage of thepharmaceutical composition may vary depending on the patient'scondition, body weight or method of administration, but in the case oforal administration, it is about 5 to 1000 mg, preferably about 10 to600 mg, more preferably about 10 to 300 mg, and particularly preferablyabout 15 to 150 mg, as the active ingredient [i.e., as the compoundrepresented by formula (I)], for an adult having a body weight of 50 kg,and the composition is administered once, or in 2 or 3 divided doses aday. In this case, the composition may also be used in combination withother suppressive agents for graft-versus-host diseases and/or rejectionassociated with organ transplantation. Specific examples of thesuppressive agent for graft-versus-host diseases and/or rejectionassociated with organ transplantation, which are used in combinationwith the compound represented by the above formula (I) or a saltthereof, include cyclosporin, tacrolimus, rapamycin, steroids,azathioprine, mycophenolate mofetil, mizoribine, etc. In the case ofusing these drugs in combination, if one of the drugs interferes withmetabolism of other drugs, the dosage of each drug is to beappropriately adjusted, but in general, the dosage for administration ofa single drug is employed for each of the drugs.

When the compound represented by formula (I) described above or a saltthereof is used for diseases other than the suppressive agents forgraft-versus-host diseases and/or rejection associated with organtransplantation, the daily dosage thereof may vary depending on the kindof the disease to be treated, the patient's condition, body weight, ormethod of administration. But, in the case of oral administration, thedosage is about 5 to 1000 mg, preferably about 10 to 600 mg, morepreferably about 10 to 300 mg, and particularly preferably about 15 to150 mg, as the active ingredient [i.e., as the compound represented byformula (I)], for an adult having a body weight of 50 kg, and thecomposition is administered once, or in 2 or 3 divided doses a day. Whenthe compound is used in combination with other drugs, the dosage of theother drugs is appropriately selected in a range of, for example, about1/200 to ½ or more and about 2 to 3 times or less of a general dosage.Further, in the case of using the compound in combination with two ormore drugs, if one of the drugs interferes with metabolism of the otherdrugs, the dosage of each drug is to be appropriately adjusted, but ingeneral, the dosage for administration of a single drug is employed foreach of the drugs.

Furthermore, the compound represented by formula (I) or a salt thereofcan be also included in or used in combination with blood fortransfusion or blood derivatives. Blood for transfusion or bloodderivatives are usually produced by mixing blood obtained from aplurality of persons, and in some cases, cells infected by HIV virus maybe co-present with HIV-uninfected cells. In such a case, there is fearfor infection of the uninfected cells. Thus, when the compoundrepresented by formula (I) of the present invention is added to bloodfor transfusion or a blood derivative, it is possible to prevent orcontrol infection and proliferation of the virus. Especially, uponstorage of blood derivatives, addition of the compound represented byformula (I) of the present invention is effective for prevention orcontrol of infection and proliferation of the virus. In addition, whenblood for transfusion or a blood derivative contaminated with HIV virusis administered to a person, infection and proliferation of the HIVvirus in the body of the person administered with blood for transfusionor a blood derivative can be prevented by the compound represented byformula (I) that has been added to the blood or blood derivative. Forexample, in the case of orally administering the compound to an adult(body weight of about 60 kg) for preventing HIV infection upon bloodtransfusion and use of blood derivatives, the dosage for a singleadministration is usually in a range of about 0.02 to 50 mg/kg,preferably about 0.05 to 30 mg/kg, and more preferably about 0.1 to 10mg/kg, as the CCR antagonist, and the compound is preferablyadministered in about 1 to about 3 doses a day. As a matter of fact, therange of dosage can be adjusted on the basis of the unit dosagenecessary for dividing the daily dosage; however, as described above,the dosage can be determined by taking into consideration of the natureand severity of the disease, the patient's age, body weight, generalhealth condition, gender, meal, administration time, method ofadministration, excretion rate and other factors. In this case, themethod of administration can be also appropriately selected, and theabove-described prophylactic agent for HIV infection of the presentinvention may be added directly to the blood or blood derivative to betransfused, prior to blood transfusion or use of blood derivative. Insuch a case, the addition of the compound is preferably carried outimmediately before to 24 hours before, preferably immediately before to12 hours before, and more preferably immediately before to 6 hoursbefore, the transfusion or use of blood derivative.

When the prophylactic agent for HIV infection of the present inventionis further administered in addition to the blood or blood derivative tobe transfused, at the time of blood transfusion or use of bloodderivative, the agent is preferably administered from 1 hour before tosimultaneously with transfusion or use of blood derivative, and morepreferably, the agent is administered 1 to 3 times per day, continuouslyfor 4 weeks.

Moreover, when the compound represented by formula (I) or a salt thereofis used in combination with a reverse transcriptase inhibitor and/or aprotease inhibitor, the dosage of the reverse transcriptase inhibitor orthe protease inhibitor is appropriately selected in a range of, forexample, about 1/200 to ½ or more and about 2 to 3 times or less of thegeneral dosage.

The general dosages for representative reverse transcriptase inhibitorsand protease inhibitors are as follows:

zidovudine: 100 mg

didanosine: 125-200 mg

zalcitabine: 0.75 mg

lamivudine: 150 mg

stavudine: 30-40 mg

saquinavir: 600 mg

ritonavir: 600 mg

indinavir: 800 mg

nelfinavir: 750 mg

Also, a specific embodiment of the case where the compound representedby formula (I) or a salt thereof is used in combination with a reversetranscriptase inhibitor and/or a protease inhibitor will be describedbelow.

(1) About 10 to 300 mg of the compound represented by formula (I) or asalt thereof and about 50 to 200 mg of zidovudine for an adult (bodyweight of 50 kg), are administered in combination to the same subject.Each drug may be administered simultaneously or separately with a timeinterval of 12 hours or less.

(2) About 10 to 300 mg of the compound represented by formula (I) or asalt thereof and about 300 to 1200 mg of saquinavir for an adult (bodyweight of 50 kg), are administered in combination to the same subject.Each drug may be administered simultaneously or separately with a timeinterval of 12 hours or less.

The following Examples, Reference Examples, Experimental Example andFormulation Examples further illustrate the present invention in detailbut are not to be construed to limit the scope thereof.

EXAMPLE 1 Preparation of Compound 1

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (0.89 g) was added 1 N hydrochloricacid (5 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% potassium carbonate solution (5ml), followed by extraction with ethyl acetate-2-propanol (4:1) threetimes. The organic layer was washed with saturated brine and dried overmagnesium sulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline as acolorless amorphous material.

To a solution of(2E)-3-[4-azepan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]acrylicacid (450 mg) in THF (10 ml) were added thionyl chloride (0.11 ml) andDMF (one drop) at room temperature, and the mixture was stirred for 1hour. After concentration under reduced pressure, a solution of theresidue in THF (30 ml) was added dropwise to a suspension of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline andtriethylamine (0.85 ml) in THF (20 ml) at room temperature. Afterstirring the resulting mixture at room temperature for 20 hours, waterwas added thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with an aqueous 5% acetic acid solution, anaqueous saturated sodium hydrogen carbonate solution and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was separated and purified by columnchromatography (basic silica gel, ethyl acetate) to give(S)-(2E)-3-[4-azepan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 1) (67.7 mg) as a yellow amorphous material.

¹H-NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.2 Hz), 0.91 (3H, t, J=7.5Hz), 1.31-1.46 (2H, m), 1.51-1.88 (12H, m), 3.23-3.26 (4H, m), 3.56 (2H,t, J=6.8 Hz), 3.76-3.84 (4H, m), 4.02 (1H, d, J=14.1 Hz), 4.10-4.18 (3H,m), 6.52-6.58 (2H, m), 6.98 (2H, d, J=9.0 Hz), 7.15 (1H, d, J=8.4 Hz),7.35 (2H, d, J=8.7 Hz), 7.45-7.50 (4H, m), 7.64 (1H, d, J=2.1 Hz), 7.79(2H, d, J=8.7 Hz), 8.05 (1H, s), 8.22 (1H, d, J=15.3 Hz).

EXAMPLE 2 Preparation of Compound 2

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (0.93 g) was added 1 N hydrochloricacid (5 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% potassium carbonate solution (5ml), followed by extraction with ethyl acetate-2-propanol (4:1) threetimes. The organic layer was washed with saturated brine and dried overmagnesium sulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline as acolorless amorphous material.

To a solution of(2E)-3-[4-azepan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]-2-methylacrylicacid (0.48 g) in THF (10 ml) were added thionyl chloride (0.12 ml) andDMF (one drop) at room temperature, and the mixture was stirred for 1.5hours. After concentration under reduced pressure, a solution of theresidue in THF (30 ml) was added dropwise to a suspension of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline andtriethylamine (0.89 ml) in THF (30 ml) at room temperature. Afterstirring the resulting mixture at room temperature for 2 days, water wasadded thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with an aqueous 5% acetic acid solution, anaqueous saturated sodium hydrogen carbonate solution and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was separated and purified by columnchromatography (basic silica gel, ethyl acetate) to give(S)-(2E)-3-[4-azepan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 2) (77.2 mg) as a yellow amorphous material.

¹H-NMR (300 MHz, CDCl₃) δ 0.92 (3H, t, J=7.5 Hz), 0.93 (3H, t, J=7.4Hz), 1.32-1.45 (2H, m), 1.48-1.84 (12H, m), 2.26 (3H, d, J=1.2 Hz),3.22-3.26 (4H, m), 3.55 (2H, t, J=6.8 Hz), 3.77-3.83 (4H, m), 4.04 (1H,d, J=14.1 Hz), 4.11 (1H, d, J=14.1 Hz), 4.16 (2H, t, J=5.0 Hz), 6.60(1H, s), 6.99 (2H, d, J=9.0 Hz), 7.13 (1H, d, J=8.1 Hz), 7.37-7.48 (7H,m), 7.60 (1H, s), 7.76-7.86 (3H, m).

IR (KBr) 3102, 1669, 1590, 1518, 1489, 1456, 1397, 1312, 1246, 1121,1047, 822 cm^(−1.)

EXAMPLE 3 Preparation of Compound 3

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (0.95 g) was added 1 N hydrochloricacid (5 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% potassium carbonate solution (5ml), followed by extraction with ethyl acetate-2-propanol (4:1) threetimes. The organic layer was washed with saturated brine and dried overmagnesium sulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline as acolorless amorphous material.

To a solution of(2E)-3-[4-azocan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]acrylicacid (0.50 g) in THF (10 ml) were added oxalic chloride (0.106 ml) andDMF (one drop) at room temperature, and the mixture was stirred for 1hour. The reaction mixture was added dropwise to a suspension of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline andtriethylamine (0.92 ml) in THF (20 ml) at room temperature. Afterstirring the resulting mixture at room temperature for 4 days, water wasadded thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with an aqueous 5% acetic acid solution, anaqueous saturated sodium hydrogen carbonate solution and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was separated and purified by columnchromatography (basic silica gel, ethyl acetate) to give(S)-(2E)-3-[4-azocan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 3) (280 mg) as a yellow amorphous material.

[α]_(D)=−147.7° (c=0.467%, ethanol solution)

¹H-NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.5 Hz), 0.94 (3H, t, J=7.5Hz), 1.33-1.44 (2H, m), 1.50-1.82 (14H, m), 3.20-3.29 (4H, m), 3.56 (2H,t, J=6.6 Hz), 3.76-3.83 (4H, m) 4.01 (1H, d, J=13.8 Hz), 4.10-4.18 (3H,m), 6.53 (1H, d, J=15.5 Hz), 6.57 (1H, s), 6.98 (2H, d, J=9.0 Hz), 7.21(1H, d, J=8.7 Hz), 7.34 (2H, d, J=8.7 Hz), 7.45-7.51 (4H, m), 7.63 (1H,d, J=2.1 Hz), 7.79 (2H, d, J=8.7 Hz), 8.20 (1H, s), 8.29 (1H, d, J=15.5Hz).

IR (KBr) 3102, 1686, 1590, 1534, 1491, 1453, 1397, 1343, 1248, 1167,1121, 1047, 829 cm⁻¹

Elementary analysis C₄₁H₅₂N₄O₄S.0.5H₂O, Calcd. C, 69.76; H, 7.57; N,7.94. Found. C, 69.73; H, 7.45; N, 7.97.

EXAMPLE 4 Preparation of Compound 4

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (0.93 g) was added 1 N hydrochloricacid (5 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% potassium carbonate solution (5ml), followed by extraction with ethyl acetate-2-propanol (4:1) threetimes. The organic layer was washed with saturated brine and dried overmagnesium sulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline as acolorless amorphous material.

To a solution of(2E)-3-[4′-(2-butoxyethoxy)-4-(diisobutylamino)-1,1′-biphenyl-3-yl]acrylicacid (0.50 g) in THF (10 ml) were added oxalic chloride (0.10 ml) andDMF (one drop) at room temperature, and the mixture was stirred for 1hour. The reaction mixture was added dropwise to a suspension of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline andtriethylamine (0.89 ml) in THF (30 ml) at room temperature. Afterstirring the resulting mixture at room temperature for 20 hours, waterwas added thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with an aqueous 5% acetic acid solution, anaqueous saturated sodium hydrogen carbonate solution and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was separated and purified by columnchromatography (basic silica gel, ethyl acetate) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-(diisobutylamino)-1,1′-biphenyl-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 4) (179.3 mg) as a yellow amorphous material.

[α]_(D)=−151.2° (c=0.491%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.86-0.97 (18H, m), 1.31-1.47 (2H, m),1.51-1.93 (6H, m), 2.86 (4H, d, J=7.4 Hz), 3.56 (2H, t, J=6.6 Hz),3.74-3.84 (4H, m), 4.01 (1H, d, J=14.4 Hz), 4.09-4.19 (3H, m), 6.57 (1H,d, J=15.4 Hz), 6.59 (1H, s), 6.98 (2H, d, J=8.6 Hz), 7.19 (1H, d, J=8.8Hz), 7.34 (2H, d, J=8.4 Hz), 7.46-7.52 (4H, m), 7.67 (1H, d, J=2.2 Hz),7.80 (2H, d, J=8.8 Hz), 8.14 (1H, s), 8.28 (1H d, J=15.4 Hz).

IR (KBr) 3103, 1686 1624, 1591, 1489, 1466, 1399, 1343, 1250, 1167,1121, 1088, 1047, 997, 831 cm⁻¹

Elementary analysis C₄₂H₅₆N₄O₄S.0.5H₂O, Calcd. C, 69.87; H, 7.96; N,7.76. Found. C, 69.77; H, 7.79; N, 7.57.

EXAMPLE 5 Preparation of Compound 5

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (0.95 g) was added 1 N hydrochloricacid (5 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% potassium carbonate solution (5ml), followed by extraction with ethyl acetate-2-propanol (4:1) threetimes. The organic layer was washed with saturated brine and dried overmagnesium sulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline as acolorless amorphous material.

To a solution of(2E)-3-[4′-(2-butoxyethoxy)-4-[isobutyl(propyl)amino]-1,1′-biphenyl-3-yl]acrylicacid (0.50 g) in THF (10 ml) were added oxalic chloride (0.106 ml) andDMF (one drop) at room temperature, and the mixture was stirred for 1hour. The reaction mixture was added dropwise to a suspension of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline andtriethylamine (0.92 ml) in THF (30 ml) at room temperature. Afterstirring the resulting mixture at room temperature for 20 hours, waterwas added thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with an aqueous 5% acetic acid solution, anaqueous saturated sodium hydrogen carbonate solution and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was separated and purified by columnchromatography (basic silica gel, ethyl acetate) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-[isobutyl(propyl)amino]-1,1′-biphenyl-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 5) (175.0 mg) as a yellow amorphous material.

[α]_(D)=−145.3° (c=0.487%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.79-0.97 (15H, m), 1.30-1.86 (9H, m),2.87-3.00 (4H, m), 3.56 (2H, t, J=6.8 Hz), 3.74-3.84 (4H, m), 4.01 (1H,d, J=13.8 Hz), 4.10-4.19 (3H, m), 6.58 (1H, s), 6.60 (1H, d, J=15.6 Hz),6.98 (2H, d, J=8.8 Hz), 7.16 (1H, d, J=8.4 Hz), 7.34 (2H, d, J=8.8 Hz),7.45-7.50 (4H, m), 7.67 (1H, d, J=2.2 Hz), 7.80 (2H, d, J=8.8 Hz) 8.26(1H, d, J=15.6 Hz), 8.28 (1H, s).

IR (KBr) 3104, 1686, 1624, 1591, 1537, 1487, 1399, 1343, 1250, 1169,1119, 1088, 1049, 824 cm⁻¹

Elementary analysis C₄₁H₅₄N₄O₄S.0.5H₂O, Calcd. C, 69.56; H, 7.83; N,7.91. Found. C, 69.47; H, 7.82; N, 7.93.

EXAMPLE 6 Preparation of Compound 6

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.88 g) was added 1 N hydrochloricacid (10 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% potassium carbonate solution (10ml), followed by extraction with ethyl acetate-2-propanol (4:1) threetimes. The organic layer was washed with saturated brine and dried overmagnesium sulfate, which was concentrated under reduced pressure togive. (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline as acolorless amorphous material. To a solution of(2E)-3-[4′-(2-butoxyethoxy)-4-[isobutyl(methyl)amino]-1,1′-biphenyl-3-yl]acrylicacid (1.0 g) in THF (10 ml) were added oxalic chloride (0.23 ml) and DMF(one drop) at room temperature, and the mixture was stirred for 1 hour.The reaction mixture was added dropwise to a suspension of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline andtriethylamine (1.84 ml) in THF (20 ml) at room temperature. Afterstirring the resulting mixture at room temperature for 3 days, water wasadded thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with an aqueous 5% acetic acid solution, anaqueous saturated sodium hydrogen carbonate solution and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was separated and purified by columnchromatography (basic silica gel, ethyl acetate) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-[isobutyl(methyl)amino]-1,1′-biphenyl-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 6) (362 mg) as a yellow amorphous material.

[α]_(D)=−158.1° (c=0.473%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.85-0.97 (12H, m), 1.30-1.47 (4H, m),1.52-1.78 (2H, m), 1.84-2.00 (1H, m), 2.73 (3H, s), 2.79 (2H, d, J=7.4Hz), 3.56 (2H, t, J=6.6 Hz), 3.74-3.84 (4H, m), 3.99 (1H, d, J=14.4 Hz),4.11-4.19 (3H, m), 6.56 (1H, s) 6.65 (1H, d, J=15.8 Hz), 6.97 (2H, d,J=8.8 Hz), 7.13 (1H, d, J=8.4 Hz), 7.32 (2H, d, J=8.8 Hz), 7.43-7.52(4H, m), 7.64 (1H, d, J=2.2 Hz), 7.80 (2H, d, J=8.8 Hz), 8.22 (1H, d,J=15.8 Hz), 8.63 (1H, s).

IR (KBr) 3098, 1684, 1591, 1534, 1491, 1343, 1250, 1169, 1123, 1047, 826cm⁻¹

Elementary analysis C₃₉H₅₀N₄O₄S.0.5H₂O, Calcd. C, 68.89; H, 7.56; N,8.24. Found. C, 68.83; H, 7.40; N, 8.14.

EXAMPLE 7 Preparation of Compound 7

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.82 g) was added 1 N hydrochloricacid (10 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% potassium carbonate solution (10ml), followed by extraction with ethyl acetate-2-propanol (4:1) threetimes. The organic layer was washed with saturated brine and dried overmagnesium sulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline as acolorless amorphous material. To a solution of(2E)-3-[4-azepan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]-2-ethylacrylicacid (1.0 g) in THF (10 ml) were added oxalic chloride (0.21 ml) and DMF(one drop) at room temperature, and the mixture was stirred for 1 hour.The reaction mixture was added dropwise to a suspension of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline andtriethylamine (1.76 ml) in THF (20 ml) at room temperature. Afterstirring the resulting mixture at room temperature for 20 hours, waterwas added thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with an aqueous 5% acetic acid solution, anaqueous saturated sodium hydrogen carbonate solution and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was separated and purified by columnchromatography (basic silica gel, ethyl acetate) to give(S)-(2E)-3-[4-azepan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]-2-ethyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 7) (278 mg) as a yellow amorphous material.

[α]_(D)=−123.7° (c=0.494%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.92 (3H, t, J=7.5 Hz), 0.93 (3H, t, J=7.3Hz), 1.23 (3H, t, J=7.4 Hz), 1.29-1.48 (2H, m), 1.52-1.85 (12H, m), 2.73(2H, q, J=7.4 Hz), 3.20-3.25 (4H, m), 3.55 (2H, t, J=6.8 Hz), 3.76-3.83(4H, m), 4.02 (1H, d, J=14.0 Hz), 4.07-4.19 (3H, m), 6.61 (1H, s), 6.99(2H, d, J=8.6 Hz), 7.12 (1H, d, J=8.4 Hz), 7.36-7.49 (8H, m), 7.78 (2H,d, J=8.8 Hz), 7.90 (1H, s).

IR (KBr) 3085, 1671, 1590, 1518, 1489, 1399, 1316, 1246, 1123, 1047, 820cm⁻¹

Elementary analysis C₄₂H₅₄N₄O₄S.0.5H₂O, Calcd. C, 70.07; H, 7.70; N,7.78. Found. C, 70.10; H, 7.74; N, 7.70.

EXAMPLE 8 Preparation of Compound 8

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.58 g) was added 1 N hydrochloricacid (10 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% potassium carbonate solution (10ml), followed by extraction with ethyl acetate-2-propanol (4:1) threetimes. The organic layer was washed with saturated brine and dried overmagnesium sulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline as acolorless amorphous material. To a solution of(2E)-3-[4′-(2-butoxyethoxy)-4-[ethyl(isobutyl)amino]-1,1′-biphenyl-3-yl]acrylicacid (0.71 g) in THF (10 ml) were added oxalic chloride (0.14 ml) andDMF (one drop) at room temperature, and the mixture was stirred for 1hour. The reaction mixture was added dropwise to a suspension ofaforementioned aniline and triethylamine (1.5 ml) in THF (20 ml) at 0°C. After stirring the resulting mixture at room temperature for 20hours, water was added thereto and the mixture was extracted with ethylacetate. The organic layer was washed with an aqueous 5% acetic acidsolution, an aqueous saturated sodium hydrogen carbonate solution andsaturated brine, and dried over magnesium sulfate. After concentrationunder reduced pressure, the residue was separated and purified by columnchromatography (basic silica gel, ethyl acetate) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-[ethyl(isobutyl)amino]-1,1′-biphenyl-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 8) (250.6 mg) as a yellow amorphous material.

[α]_(D)=−156.9° (c=0.485%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.85-0.97 (12H, m), 1.04 (3H, t, J=7.0 Hz),1.29-1.48 (2H, m), 1.51-1.87 (5H, m), 2.87 (2H, d, J=7.4 Hz), 3.06 (2H,q, J=7.0 Hz), 3.56 (2H, t, J=6.6 Hz), 3.74-3.84 (4H, m), 4.00 (1H, d,J=14.2 Hz), 4.10-4.19 (3H, m), 6.58 (1H, s), 6.61 (1H, d, J=15.4 Hz),6.98 (2H, d, J=8.8 Hz), 7.15 (1H, d, J=8.6 Hz), 7.33 (2H, d, J=8.6 Hz),7.44-7.52 (4H, m), 7.67 (1H, d, J=2.2 Hz), 7.79 (2H, d, J=8.6 Hz), 8.25(1H, d, J=15.4 Hz), 8.38 (1H, s).

IR (KBr) 3103, 1684, 1591, 1534, 1489, 1399, 1345, 1250, 1169, 1123,1047, 826 cm⁻¹

Elementary analysis C₄₀H₅₂N₄O₄S.0.5H₂O, Calcd. C, 69.23; H, 7.70; N,8.07. Found. C, 69.13; H, 7.65; N, 7.82.

EXAMPLE 9 Preparation of Compound 9

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.64 g) was added 1 N hydrochloricacid (10 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% potassium carbonate solution (10ml), followed by extraction with ethyl acetate-2-propanol (4:1) threetimes. The organic layer was washed with saturated brine and dried overmagnesium sulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline as acolorless amorphous material. To a solution of(2E)-3-[4′-(2-butoxyethoxy)-4-piperidin-1-yl-1,1′-biphenyl-3-yl]acrylicacid (0.80 g) in THF (10 ml) were added oxalic chloride (0.17 ml) andDMF (one drop) at 0° C., and the mixture was stirred at 0° C. for 0.5hour and then at room temperature for 1 hour. The reaction mixture wasadded dropwise to a suspension of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline andtriethylamine (1.6 ml) in THF (20 ml) at 0° C. After stirring theresulting mixture at room temperature for 18 hours, water was addedthereto and the mixture was extracted with ethyl acetate. The organiclayer was washed with an aqueous 5% acetic acid solution, an aqueoussaturated sodium hydrogen carbonate solution and saturated brine, anddried over magnesium sulfate. After concentration under reducedpressure, the residue was separated and purified by columnchromatography (basic silica gel, ethyl acetate→ethanol:ethyl acetate1:99) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-piperidin-1-yl-1,1′-biphenyl-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 9) (410.5 mg) as a yellow amorphous material.

[α]_(D)=−155.1° (c=0.504%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.89 (3H, t, J=7.4 Hz), 0.94 (3H, t, J=7.2Hz), 1.30-1.86 (12H, m), 2.89-3.00 (4H, m), 3.56 (2H, t, J=6.6 Hz),3.75-3.84 (4H, m), 4.00 (1H, d, J=13.8 Hz), 4.10-4.19 (3H, m), 6.57 (1H,s), 6.66 (1H, d, J=15.3 Hz), 6.97 (2H, d, J=8.6 Hz), 7.09 (1H, d, J=8.4Hz), 7.33 (2H, d, J=8.4 Hz), 7.43-7.53 (4H, m), 7.66 (1H, d, J=2.6 Hz),7.80 (2H, d, J=8.4 Hz), 8.17 (1H, d, J=15.3 Hz), 8.25-8.45 (1H, m).

IR (KBr) 3031, 1684, 1590, 1534, 1489, 1343, 1250, 1231, 1169, 1123,1044, 820 cm⁻¹

Elementary analysis C₃₉H₄₈N₄O₄S.0.5H₂O, Calcd. C, 69.10; H, 7.29; N,8.26. Found. C, 69.12; H, 7.25; N, 8.13.

EXAMPLE 10 Preparation of Compound 10

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.58 g) was added 1 N hydrochloricacid (10 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% potassium carbonate solution (10ml), followed by extraction with ethyl acetate-2-propanol (4:1) threetimes. The organic layer was washed with saturated brine and dried overmagnesium sulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline as acolorless amorphous material. To a solution of(2E)-3-[4′-(2-butoxyethoxy)-4-piperidin-1-yl-1,1′-biphenyl-3-yl]-2-methylacrylicacid (0.80 g) in THF (10 ml) were added oxalic chloride (0.17 ml) andDMF (one drop) at 0° C., and the mixture was stirred at 0° C. for 30minutes and then at room temperature for 1.5 hours. The reaction mixturewas added dropwise to a suspension of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline andtriethylamine (1.53 ml) in THF (20 ml) at 0° C. After stirring theresulting mixture at room temperature for 20 hours, water was addedthereto and the mixture was extracted with ethyl acetate. The organiclayer was washed with an aqueous 5% acetic acid solution, an aqueoussaturated sodium hydrogen carbonate solution and saturated brine, anddried over magnesium sulfate. After concentration under reducedpressure, the residue was separated and purified by columnchromatography (basic silica gel, ethyl acetate) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-piperidin-1-yl-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 10) (343.7 mg) as a yellow amorphous material.

[α]_(D)=−134.0° (c=0.487%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.92 (3H, t, J=7.5 Hz), 0.93 (3H, t, J=7.2Hz), 1.28-1.81 (12H, m), 2.29 (3H, d, J=1.0 Hz), 2.86-2.98 (4H, m), 3.55(2H, t, J=6.6 Hz), 3.76-3.83 (4H, m), 4.00-4.19 (4H, m), 6.60 (1H, s),6.99 (2H, d, J=8.8 Hz), 7.09 (1H, d, J=9.2 Hz), 7.31-7.49 (7H, m),7.54-7.60 (1H, m), 7.77 (2H, d, J=8.8 Hz), 7.82 (1H, s).

IR (KBr) 3032, 1661, 1591, 1522, 1487, 1453, 1310, 1233, 1178, 1125,1042, 820 cm⁻¹

Elementary analysis C₄₀H₅₀N₄O₄S.1.25H₂O, Calcd. C, 68.10; H, 7.50; N,7.94. Found. C, 68.13; H, 7.40; N, 7.87.

EXAMPLE 11 Preparation of Compound 11

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.27 g) was added 1 N hydrochloricacid (10 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% potassium carbonate solution (10ml), followed by extraction with ethyl acetate-2-propanol (4:1) threetimes. The organic layer was washed with saturated brine and dried overmagnesium sulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline as acolorless amorphous material. To a solution of(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]acrylicacid (0.60 g) in THF (10 ml) were added oxalic chloride (0.14 ml) andDMF (one drop) at 0° C., and the mixture was stirred at 0° C. for 1hour. The reaction mixture was added dropwise to a suspension of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline andtriethylamine (1.23 ml) in THF (30 ml) at 0° C. After stirring theresulting mixture at room temperature for 18 hours, water was addedthereto and the mixture was extracted with ethyl acetate. The organiclayer was washed with an aqueous 5% acetic acid solution, an aqueoussaturated sodium hydrogen carbonate solution and saturated brine, anddried over magnesium sulfate. After concentration under reducedpressure, the residue was separated and purified by columnchromatography (basic silica gel, ethyl acetate→ethanol:ethyl acetate1:49) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 11) (23 mg) as a yellow amorphous material.

¹H-NMR (200 MHz, CDCl₃) δ 0.91 (3H, t, J=7.4 Hz), 0.94 (3H, t, J=7.0Hz), 1.28-1.49 (6H, m), 1.90-2.01 (4H, m), 3.29-3.41 (4H, m), 3.56 (2H,t, J=6.6 Hz), 3.74-3.84 (4H, m), 3.99-4.19 (4H, m), 6.71 (1H, d, J=15.4Hz), 6.59 (1H, s), 6.93 (1H, d, J=8.4 Hz), 6.98 (2H, d, J=8.6 Hz),7.33-7.49 (6H, m), 7.59 (1H, d, J=2.6 Hz), 7.79 (2H, d, J=8.6 Hz), 7.84(1H, s), 8.20 (1H, d, J=15.4 Hz).

EXAMPLE 12 Preparation of Compound 12

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.64 g) was added 1 N hydrochloricacid (10 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% potassium carbonate solution (10ml), followed by extraction with ethyl acetate-2-propanol (4:1) threetimes. The organic layer was washed with saturated brine and dried overmagnesium sulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline as acolorless amorphous material. To a solution of(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]-2-methylacrylicacid (0.80 g) in THF (10 ml) were added oxalic chloride (0.18 ml) andDMF (one drop) at 0° C., and the mixture was stirred at 0° C. for 1 hourand then at room temperature for 0.5 hour. The reaction mixture wasadded dropwise to a suspension of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline andtriethylamine (1.58 ml) in THF (30 ml) at 0° C. After stirring theresulting mixture at room temperature for 20 hours, water was addedthereto and the mixture was extracted with ethyl acetate. The organiclayer was washed with an aqueous 10% acetic acid solution, an aqueoussaturated sodium hydrogen carbonate solution and saturated brine, anddried over magnesium sulfate. After concentration under reducedpressure, the residue was separated and purified by columnchromatography (basic silica gel, ethyl acetate) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 12) (488.3 mg) as a yellow amorphous material.

[α]_(D)=−123.0° (c=0.538%, ethanol solution)

¹H-NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.4 Hz), 0.93 (3H, t, J=7.1Hz), 1.29-1.47 (2H, m), 1.51-1.78 (4H, m), 1.87-1.99 (4H, m), 2.20 (3H,d, J=1.2 Hz), 3.30-3.41 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.76-3.83 (4H,m), 4.02 (1H, d, J=14.4 Hz), 4.08-4.18 (3H, m), 6.56 (1H, s), 6.91 (1H,d, J=8.4 Hz), 6.98 (2H, d, J=9.0 Hz), 7.33-7.48 (7H, m), 7.63 (1H, s),7.78 (2H, d, J=8.8 Hz), 7.85 (1H, s).

IR (KBr) 3029, 1667, 1603, 1590, 1520, 1497, 1489, 1397, 1314, 1246,1121, 912, 743 cm⁻¹

Elementary analysis C₃₉H₄₈N₄O₄S.0.5H₂O, Calcd. C, 69.10; H, 7.29; N,8.26. Found. C, 68.97; H, 7.24; N, 8.07.

EXAMPLE 13 Preparation of Compound 13

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.59 g) was added 1 N hydrochloricacid (10 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% sodium hydroxide solution (10ml), followed by extraction with ethyl acetate-2-propanol (4:1). Theorganic layer was washed with saturated brine and dried over magnesiumsulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline. To asolution of(2E)-3-[4′-(2-butoxyethoxy)-4-(4-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]acrylicacid (0.80 g) and DMF (one drop) in THF (10 ml) was added oxalicchloride (0.176 ml) at 0° C., and the mixture was stirred at roomtemperature for 1.5 hours. The solution was added dropwise to a mixtureof (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline andtriethylamine (1.52 ml) in THF (20 ml) at 0° C. After stirring theresulting mixture at room temperature for 20 hours, water was addedthereto and the mixture was extracted with ethyl acetate. The organiclayer was washed with an aqueous 10% acetic acid solution, an aqueoussodium hydrogen carbonate solution and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by column chromatography (basicsilica gel, ethyl acetate→ethanol:ethyl acetate 1:49) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-(4-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 13) (11 mg) as a yellow amorphous material.

¹H-NMR (200 MHz, CDCl₃) δ 0.87-1.03 (9H, m), 1.31-1.82 (11H, m),2.62-2.81 (2H, m), 3.13-3.26 (2H, m), 3.56 (2H, t, J=6.8 Hz), 3.75-3.84(4H, m), 3.97-4.19 (4H, m), 6.55-6.65 (2H, m), 6.99 (2H, d, J=9.0 Hz),7.10 (1H, d, J=8.8 Hz), 7.35 (2H, d, J=8.8 Hz), 7.45-7.52 (4H, m),7.65-7.69 (1H, m), 7.80 (2H, d, J=8.8 Hz), 8.17 (1H, d, J=15.4 Hz).

EXAMPLE 14 Preparation of Compound 14

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.19 g) was added 1 N hydrochloricacid (10 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% sodium hydroxide solution (10ml), followed by extraction with ethyl acetate-2-propanol (4:1). Theorganic layer was washed with saturated brine and dried over magnesiumsulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline. To asolution of(2E)-3-[4′-(2-butoxyethoxy)-4-(4-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylicacid (0.60 g) and DMF (one drop) in THF (10 ml) was added oxalicchloride (0.12 ml) at 0° C., and the mixture was stirred at roomtemperature for 10 minutes. To the reaction system were added THF (20ml) and DMF (4 ml) and the mixture was further stirred for 1 hour. Thesolution was added dropwise to a mixture of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline andtriethylamine (1.15 ml) in THF (20 ml) at 0° C. After stirring theresulting mixture at room temperature for 20 hours, water was addedthereto and the mixture was extracted with ethyl acetate. The organiclayer was washed with an aqueous 10% acetic acid solution, an aqueoussodium hydrogen carbonate solution and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by column chromatography (basicsilica gel, ethyl acetate) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-(4-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 14) (536.6 mg) as a yellow amorphous material.

[α]_(D)=−131.6° (c=0.472%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.92 (3H, t, J=7.3 Hz), 0.93 (3H, t, J=7.2Hz), 0.99 (3H, d, J=6.2 Hz), 1.26-1.81 (11H, m), 2.29 (3H, s), 2.61-2.79(2H, m), 3.12-3.25 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.75-3.83 (4H, m),4.03 (1H, d, J=14.2 Hz), 4.08-4.19 (3H, m), 6.61 (1H, s), 7.00 (2H, d,J=8.4 Hz), 7.09 (1H, d, J=9.2 Hz), 7.37-7.56 (8H, m), 7.78 (2H, d, J=8.8Hz), 7.82 (1H, s).

IR (KBr) 3185, 1669, 1607, 1590, 1518, 1487, 1312, 1248, 1225, 1121, 823cm⁻¹

Elementary analysis C₄₁H₅₂N₄O₄S.0.5H₂O, Calcd. C, 69.76; H, 7.57; N,7.94. Found. C, 69.73; H, 7.62; N, 7.85.

EXAMPLE 15 Preparation of Compound 15

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.59 g) was added 1 N hydrochloricacid (10 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% sodium hydroxide solution (10ml), followed by extraction with ethyl acetate-2-propanol (4:1). Theorganic layer was washed with saturated brine and dried over magnesiumsulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline. To asolution of(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]-2-ethylacrylicacid (0.80 g) and DMF (0.1 ml) in THF (10 ml) was added oxalic chloride(0.175 ml) at 0° C., and the mixture was stirred at room temperature for1.5 hours. The solution was added dropwise to a mixture of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline and pyridine(1.48 ml) in THF (30 ml) at 0° C. After stirring the resulting mixtureat room temperature for 20 hours, water was added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith an aqueous 10% acetic acid solution, an aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasseparated and purified by column chromatography (basic silica gel, ethylacetate) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]-2-ethyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 15) (917.6 mg) as a yellow amorphous material.

¹H-NMR (200 MHz, CDCl₃) δ 0.91 (3H, t, J=7.5 Hz), 0.93 (3H, t, J=7.1Hz), 1.22 (3H, t, J=7.5 Hz), 1.30-1.48 (2H, m), 1.55-1.79 (4H, m),1.86-2.01 (4H, m), 2.70 (2H, q, J=7.5 Hz), 3.21-3.32 (4H, m), 3.55 (2H,t, J=6.6 Hz), 3.77-3.84 (4H, m), 4.01 (1H, d, J=14.2 Hz), 4.07-4.19 (3H,m), 6.56 (1H, s), 6.91 (1H, d, J=8.4 Hz), 6.99 (2H, d, J=8.8 Hz),7.34-7.48 (8H, m), 7.79 (2H, d, J=8.8 Hz), 7.99 (1H, s).

Elementary analysis C₄₀H₅₀N₄O₄S.0.5H₂O, Calcd. C, 70.35; H, 7.38; N,8.20. Found. C, 70.31; H, 7.63; N, 8.20.

EXAMPLE 16 Preparation of Compound 16

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.64 g) was added 1 N hydrochloricacid (10 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% sodium hydroxide solution (10ml), followed by extraction with ethyl acetate-2-propanol (4:1). Theorganic layer was washed with saturated brine and dried over magnesiumsulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline. To asolution of(2E)-3-[4′-(2-butoxyethoxy)-4-(2-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]acrylicacid (0.80 g) and DMF (0.1 ml) in THF (20 ml) was added oxalic chloride(0.18 ml) at 0° C., and the mixture was stirred at room temperature for1.5 hours. The solution was added dropwise to a mixture of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline and pyridine(1.52 ml) in THF (20 ml) at 0° C. After stirring the resulting mixtureat room temperature for 3 days, water was added thereto and the mixturewas extracted with ethyl acetate. The organic layer was washed with anaqueous 10% acetic acid solution, an aqueous sodium hydrogen carbonatesolution and saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (basic silica gel, ethylacetate→ethanol:ethyl acetate 1:49) to give(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(2-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 16) (976 mg) as a yellow amorphous material.

[α]_(D)=−155.4° (c=0.525%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.89 (3H, t, J=7.3 Hz), 0.94 (3H, t, J=7.3Hz), 1.11 (3H, d, J=6.0 Hz), 1.29-1.49 (2H, m), 1.53-2.01 (7H, m),2.08-2.28 (1H, m), 2.93-3.08 (1H, m), 3.56 (2H, t, J=6.6 Hz), 3.64-3.84(6H, m), 3.99 (1H, d, J=14.2 Hz), 4.07-4.19 (3H, m), 6.54 (1H, s), 6.56(1H, d, J=15.4 Hz), 6.97 (2H, d, J=8.8 Hz), 6.99 (1H, d, J=8.4 Hz), 7.32(2H, d, J=8.8 Hz), 7.42-7.49 (4H, m), 7.59 (1H, d, J=2.2 Hz), 7.80 (2H,d, J=8.8 Hz), 8.13 (1H, d, J=15.4 Hz), 8.74-8.78 (1H, m).

Elementary analysis C₃₉H₄₈N₄O₄S.0.5H₂O, Calcd. C, 69.10; H, 7.29; N,8.26. Found. C, 68.96; H, 7.43; N, 8.21.

EXAMPLE 17 Preparation of Compound 17

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.59 g) was added 1 N hydrochloricacid (10 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% sodium hydroxide solution (10ml), followed by extraction with ethyl acetate-2-propanol (4:1). Theorganic layer was washed with saturated brine and dried over magnesiumsulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline. To asolution of(2E)-3-[4′-(2-butoxyethoxy)-4-(2-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylicacid (0.80 g) and DMF (0.1 ml) in THF (20 ml) was added oxalic chloride(0.175 ml) at 0° C., and the mixture was stirred at room temperature for1.5 hours. The solution was added dropwise to a mixture of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline and pyridine(1.48 ml) in THF (20 ml) at 0° C. After stirring the resulting mixtureat room temperature for 64 hours, water was added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith an aqueous 10% acetic acid solution, water, an aqueous sodiumhydrogen carbonate solution and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by column chromatography (basicsilica gel, ethyl acetate→ethanol:ethyl acetate 1:49) to give(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(2-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 17) (427 mg) as a yellow amorphous material.

[α]_(D)=−137.9° (c=0.501%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.89 (3H, t, J=7.3 Hz), 0.93 (3H, t, J=7.4Hz), 1.12 (3H, d, J=5.8 Hz), 1.26-1.46 (2H, m), 1.51-1.95 (7H, m),2.10-2.27 (4H, m), 2.84-3.04 (1H, m), 3.45-3.63 (3H, m), 3.73-3.91 (5H,m), 4.03 (1H, d, J=13.2 Hz), 4.08-4.18 (3H, m), 6.56 (1H, s), 6.96 (1H,d, J=8.4 Hz), 6.98 (2H, d, J=8.4 Hz), 7.35-7.53 (8H, m), 7.78 (2H, d,J=8.4 Hz), 7.82 (1H, s).

IR (KBr) 3026, 1669, 1590, 1518, 1489, 1312, 1248, 1119, 820 cm⁻¹

Elementary analysis C₄₀H₅₀N₄O₄S.0.5H₂O, Calcd. C, 69.43; H, 7.43; N,8.10. Found. C, 69.24; H, 7.73; N, 7.97.

EXAMPLE 18 Preparation of Compound 18

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.63 g) was added 1 N hydrochloricacid (10 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% sodium hydroxide solution (10ml), followed by extraction with ethyl acetate-2-propanol (4:1). Theorganic layer was washed with saturated brine and dried over magnesiumsulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline. To asolution of(2E)-3-[4′-(2-butoxyethoxy)-4-morpholin-4-yl-1,1′-biphenyl-3-yl]acrylicacid (0.80 g) and DMF (0.1 ml) in THF (20 ml) was added oxalic chloride(0.18 ml) at 0° C., and the mixture was stirred at room temperature for1.5 hours. The solution was added dropwise to a mixture of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline and pyridine(1.52 ml) in THF (20 ml) at 0° C. After stirring the resulting mixtureat room temperature for 20 hours, water was added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith an aqueous 10% acetic acid solution, water, an aqueous sodiumhydrogen carbonate solution and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by column chromatography (basicsilica gel, ethyl acetate→ethanol:ethyl acetate 1:49) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-morpholin-4-yl-1,1′-biphenyl-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 18) (1.17 g) as a yellow amorphous material.

[α]_(D)=−158.3° (c=0.551%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.88 (3H, t, J=7.3 Hz), 0.94 (3H, t, J=7.3Hz), 1.31-1.49 (2H, m), 1.56-1.80 (4H, m), 2.92-3.05 (4H, m), 3.57 (2H,t, J=6.6 Hz), 3.80-3.98 (8H, m), 4.11-4.23 (4H, m), 6.48 (1H, s), 6.73(1H, d, J=13.7 Hz), 6.96 (2H, d, J=8.4 Hz), 7.10 (1H, d, J=8.4 Hz), 7.30(2H, d, J=8.8 Hz), 7.43 (2H, d, J=8.8 Hz), 7.50-7.55 (2H, m), 7.63 (1H,d, J=1.8 Hz), 7.80 (2H, d, J=8.8 Hz), 8.19 (1H, d, J=15.7 Hz), 9.23-9.34(1H, m).

Elementary analysis C₃₈H₄₆N₄O₅S.0.5H₂O, Calcd. C, 67.13; H, 6.97; N,8.24. Found. C, 67.07; H, 7.10; N, 7.97.

EXAMPLE 19 Preparation of Compound 19

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.69 g) was added 1 N hydrochloricacid (10 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% sodium hydroxide solution (10ml), followed by extraction with ethyl acetate-2-propanol (4:1). Theorganic layer was washed with saturated brine and dried over magnesiumsulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline. To asolution of(2E)-3-[4′-(2-butoxyethoxy)-4-[methyl(propyl)amino]-1,1′-biphenyl-3-yl]acrylicacid (0.80 g) and DMF (0.1 ml) in THF (20 ml) was added oxalic chloride(0.18 ml) at 0° C., and the mixture was stirred at room temperature for2 hours. The solution was added dropwise to a mixture of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline and pyridine(1.57 ml) in THF (20 ml) at 0° C. After stirring the resulting mixtureat room temperature for 18 hours, water was added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith an aqueous 10% acetic acid solution, water, an aqueous sodiumhydrogen carbonate solution and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by column chromatography (basicsilica gel, ethyl acetate→ethanol:ethyl acetate 1:49) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-[methyl(propyl)amino]-1,1′-biphenyl-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 19) (1.17 g) as a yellow amorphous material.

[α]_(D)=−161.9° (c=0.486%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.85-0.97 (9H, m), 1.32-1.47 (2H, m),1.52-1.81 (6H, m), 2.77 (3H, s), 2.91-2.98 (2H, m), 3.57 (2H, t, J=6.6Hz), 3.75-3.85 (4H, m), 3.99 (1H, d, J=14.6 Hz), 4.12-4.19 (3H, m), 6.55(1H, s), 6.66 (1H, d, J=15.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.12 (1H, d,J=8.6 Hz), 7.32 (2H, d, J=8.8 Hz), 7.43-7.52 (4H, m), 7.63 (1H, d, J=2.2Hz), 7.80 (2H, d, J=8.8 Hz), 8.18 (1H, d, J=15.8 Hz), 8.64-8.75 (1H, m).

Elementary analysis C₃₈H₄₈N₄O₄S.0.25H₂O, Calcd. C, 69.01; H, 7.39; N,8.47. Found. C, 69.17; H, 7.70; N, 8.30.

EXAMPLE 20 Preparation of Compound 20

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.59 g) was added 1 N hydrochloricacid (10 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% sodium hydroxide solution (10ml), followed by extraction with ethyl acetate-2-propanol (4:1). Theorganic layer was washed with saturated brine and dried over magnesiumsulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline.

To a solution of(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]acrylicacid (0.80 g) and DMF (0.1 ml) in THF (20 ml) was added oxalic chloride(0.175 ml) at 0° C., and the mixture was stirred at room temperature for1.5 hours. The solution was added dropwise to a mixture of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline and pyridine(1.48 ml) in THF (20 ml) at 0° C. After stirring the resulting mixtureat room temperature for 64 hours, water was added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith an aqueous 10% acetic acid solution, water, an aqueous sodiumhydrogen carbonate solution and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by column chromatography (basicsilica gel, ethyl acetate) to give(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 20) (1.03 g) as a yellow amorphous material.

[α]_(D)=−158.3° (c=0.508%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.85-0.97 (9H, m), 1.30-1.49 (2H, m),1.55-2.04 (9H, m), 2.33-2.44 (1H, m), 2.52-2.73 (1H, m), 3.04-3.21 (2H,m), 3.56 (2H, t, J=6.6 Hz), 3.75-3.84 (4H, m), 3.99 (1H, d, J=14.4 Hz),4.11-4.19 (3H, m), 6.55 (1H, s), 6.69 (1H, d, J=15.6 Hz), 6.97 (2H, d,J=8.8 Hz), 7.09 (1H, d, J=8.4 Hz), 7.33 (2H, d, J=8.8 Hz), 7.43-7.53(4H, m), 7.65 (1H, d, J=2.2 Hz), 7.80 (2H, d, J=8.8 Hz), 8.16 (1H, d,J=15.6 Hz), 8.47-8.60 (1H, m).

Elementary analysis C₄₀H₅₀N₄O₄S.0.5H₂O, Calcd. C, 69.43; H, 7.43; N,8.10. Found. C, 69.58; H, 7.44; N, 7.92.

EXAMPLE 21 Preparation of Compound 21

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.59 g) was added 1 N hydrochloricacid (10 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% sodium hydroxide solution (10ml), followed by extraction with ethyl acetate-2-propanol (4:1). Theorganic layer was washed with saturated brine and dried over magnesiumsulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline. To asolution of(2E)-3-[4′-(2-butoxyethoxy)-4-(2-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]acrylicacid (0.80 g) and DMF (0.1 ml) in THF (20 ml) was added oxalic chloride(0.175 ml) at 0° C., and the mixture was stirred at room temperature for1.5 hours. The solution was added dropwise to a mixture of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline and pyridine(1.48 ml) in THF (20 ml) at 0° C. After stirring the resulting mixtureat room temperature for 2 days, water was added thereto and the mixturewas extracted with ethyl acetate. The organic layer was washed with anaqueous 10% acetic acid solution, water, an aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasseparated and purified by column chromatography (basic silica gel, ethylacetate) to give(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(2-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 21) (0.99 g) as a yellow amorphous material.

[α]_(D)=−156.9° (c=0.495%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.85-0.97 (9H, m), 1.28-1.97 (12H, m),2.54-2.75 (1H, m), 2.93-3.24 (2H, m), 3.57 (2H, t, J=6.6 Hz), 3.74-3.85(4H, m), 3.99 (1H, d, J=14.4 Hz), 4.11-4.19 (3H, m), 6.56 (1H, s), 6.69(1H, d, J=15.8 Hz), 6.98 (2H, d, J=8.8 Hz), 7.18 (1H, d, J=8.0 Hz), 7.32(2H, d, J=8.4 Hz), 7.45-7.54 (4H, m), 7.69 (1H, d, J=2.2 Hz), 7.81 (2H,d, J=8.4 Hz), 8.35 (1H, d, J=15.8 Hz), 8.63 (1H, br s).

Elementary analysis C₄₀H₅₀N₄O₄S.0.5H₂O, Calcd. C, 69.43; H, 7.43; N,8.10. Found. C, 69.17; H, 7.42; N, 7.90.

EXAMPLE 22 Preparation of Compound 22

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.02 g) was added 1 N hydrochloricacid (7.0 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% sodium hydroxide solution (7.0ml), followed by extraction with ethyl acetate-2-propanol (4:1). Theorganic layer was washed with saturated brine and dried over magnesiumsulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline. To asolution of(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]acrylicacid (0.50 g) and DMF (0.1 ml) in THF (10 ml) was added oxalic chloride(0.11 ml) at 0° C., and the mixture was stirred at 0° C. for 40 minutes.The solution was added dropwise to a mixture of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline and pyridine(0.95 ml) in THF (20 ml) at 0° C. After stirring the resulting mixtureat room temperature for 3 days, water was added thereto and the mixturewas extracted with ethyl acetate. The organic layer was washed with anaqueous 10% acetic acid solution, water, an aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasseparated and purified by column chromatography (basic silica gel, ethylacetate→ethanol:ethyl acetate 1:49) to give(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 22) (511 mg) as a yellow amorphous material.

[α]_(D)=−164.8° (c=0.484%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.87 (3H, t, J=7.3 Hz), 0.93 (3H, t, J=7.3Hz), 1.11 (3H, d, J=6.6 Hz), 1.30-1.49 (2H, m), 1.55-1.82 (5H, m),1.98-2.44 (2H, m), 2.98-3.07 (1H, m), 3.28-3.51 (3H, m), 3.56 (2H, t,J=6.6 Hz), 3.74-3.84 (4H, m), 3.97 (1H, d, J=14.4 Hz), 4.13-4.19 (3H,m), 6.50 (1H, d, J=15.0 Hz), 6.52 (1H, s), 6.86 (1H, d, J=8.8 Hz), 6.95(2H, d, J=8.8 Hz), 7.30 (2H, d, J=8.8 Hz), 7.40-7.53 (5H, m), 7.80 (2H,d, J=8.8 Hz), 8.17 (1H, d, J=15.0 Hz), 9.09 (1H, s).

EXAMPLE 23 Preparation of Compound 23

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.59 g) was added 1 N hydrochloricacid (10.0 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% sodium hydroxide solution (10.0ml), followed by extraction with ethyl acetate-2-propanol (4:1). Theorganic layer was washed with saturated brine and dried over magnesiumsulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline. To asolution of(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylicacid (0.80 g) and DMF (0.1 ml) in THF (20 ml) was added oxalic chloride(0.17 ml) at 0° C., and the mixture was stirred at room temperature for1.5 hours. The solution was added dropwise to a mixture of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline and pyridine(1.48 ml) in THF (20 ml) at 0° C. After stirring the resulting mixtureat room temperature for 20 hours, water was added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith an aqueous 10% acetic acid solution, water, an aqueous sodiumhydrogen carbonate solution and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by column chromatography (basicsilica gel, ethyl acetate→ethanol:ethyl acetate 1:49) to give(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 23) (990 mg) as a yellow amorphous material.

[α]_(D)=−132.3° (c=0.498%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.91 (3H, t, J=7.4 Hz), 0.93 (3H, t, J=7.1Hz), 1.11 (3H, d, J=6.6 Hz), 1.30-1.48 (2H, m), 1.55-1.84 (5H, m),1.98-2.44 (5H, m), 2.88-2.96 (1H, m), 3.17-3.48 (3H, m), 3.55 (2H, t,J=6.6 Hz), 3.76-3.83 (4H, m), 4.02 (1H, d, J=14.2 Hz), 4.08-4.18 (3H,m), 6.56 (1H, s), 6.87 (1H, d, J=8.6 Hz), 6.98 (2H, d, J=8.8 Hz),7.32-7.47 (7H, m), 7.63 (1H, s), 7.78 (2H, d, J=8.8 Hz), 7.86 (1H, s).

EXAMPLE 24 Preparation of Compound 24

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.53 g) was added 1 N hydrochloricacid (10.0 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% sodium hydroxide solution (10.0ml), followed by extraction with ethyl acetate-2-propanol (4:1). Theorganic layer was washed with saturated brine and dried over magnesiumsulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline. To asolution of(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylicacid (0.80 g) and DMF (0.1 ml) in THF (20 ml) was added oxalic chloride(0.17 ml) at 0° C., and the mixture was stirred at room temperature for1.5 hours. The solution was added dropwise to a mixture of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline and pyridine(1.42 ml) in THF (20 ml) at 0° C. After stirring the resulting mixtureat room temperature for 4 days, water was added thereto and the mixturewas extracted with ethyl acetate. The organic layer was washed with anaqueous 10% acetic acid solution, water, an aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasseparated and purified by column chromatography (basic silica gel, ethylacetate→ethanol:ethyl acetate 1:49) to give(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 24) (0.76 g) as a yellow amorphous material.

[α]_(D)=−127.6° (c=0.488%, ethanol solution).

¹H-NMR (200 MHz, CDCl₃) δ 0.91 (3H, t, J=7.5 Hz), 0.93 (3H, t, J=7.4Hz), 1.28-1.48 (2H, m), 1.51-1.83 (4H, m), 2.03-2.23 (5H, m), 3.12-3.51(7H, m), 3.55 (2H, t, J=6.6 Hz), 3.75-3.83 (4H, m), 3.95-4.19 (5H, m),6.59 (1H, s), 6.93 (1H, d, J=8.8 Hz), 6.99 (2H, d, J=9.0 Hz), 7.35-7.48(7H, m), 7.57 (1H, s), 7.78 (2H, d, J=8.8 Hz), 7.95 (1H, s).

EXAMPLE 25 Preparation of Compound 25

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.80 g) was added 1 N hydrochloricacid (10.0 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% sodium hydroxide solution (10.0ml), followed by extraction with ethyl acetate-2-propanol (4:1). Theorganic layer was washed with saturated brine and dried over magnesiumsulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline. To asolution of(2E)-3-[4-[3-(acetoxy)pyrrolidin-1-yl-4′-(2-butoxyethoxy)]-1,1′-biphenyl-3-yl]acrylicacid (1.0 g) and DMF (0.1 ml) in THF (20 ml) was added oxalic chloride(0.20 ml) at 0° C., and the mixture was stirred at 0° C. for 2 hours.The solution was added dropwise to a mixture of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline and pyridine(1.68 ml) in THF (20 ml) at 0° C. After stirring the resulting mixtureat room temperature for 3 days, water was added thereto and the mixturewas extracted with ethyl acetate. The organic layer was washed with anaqueous 10% acetic acid solution, water, an aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasseparated and purified by column chromatography (basic silica gel, ethylacetate) to give(S)-(2E)-3-[4-[3-(acetoxy)pyrrolidin-1-yl-4′-(2-butoxyethoxy)]-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 25) (739.3 mg) as a yellow amorphous material.

[α]_(D)=−127.5° (c=0.493%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.91 (3H, t, J=7.6 Hz), 0.93 (3H, t, J=7.1Hz), 1.25-1.46 (2H, m), 1.51-1.83 (4H, m), 2.00-2.35 (8H, m), 3.17-3.31(2H, m), 3.42-3.67 (4H, m), 3.76-3.83 (4H, m), 4.02 (1H, d, J=14.2 Hz),4.08-4.19 (3H, m), 5.26-5.36 (1H, m), 6.57 (1H, s), 6.92 (1H, d, J=8.6Hz), 6.99 (2H, d, J=8.8 Hz), 7.35-7.48 (7H, m), 7.63 (1H, s), 7.78 (2H,d, J=8.8 Hz), 7.86 (1H, s).

EXAMPLE 26 Preparation of Compound 26

To a solution of(S)-(2E)-3-[4-[3-(acetoxy)pyrrolidin-1-yl-4′-(2-butoxyethoxy)]-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(640 mg) in ethanol (10 ml) was added a 1 N aqueous sodium hydroxidesolution (1.5 ml) at room temperature. After stirring the mixture atroom temperature for 20 hours, ethanol was distilled off under reducedpressure, which was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine and dried over magnesium sulfate.After concentration under reduced pressure, the residue was separatedand purified by column chromatography (basic silica gel, ethanol:ethylacetate 1:49) to give(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-[3-hydroxypyrrolidin-1-yl-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 26) (500 mg) as a yellow amorphous material.

[α]_(D)=−131.4° (c=0.488%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.89 (3H, t, J=7.8 Hz) 0.93 (3H, t, J=7.0 Hz),1.29-1.49 (2H, m), 1.54-1.82 (4H, m), 1.91-2.32 (5H, m), 3.12-3.38 (3H,m), 3.42-3.59 (3H, m), 3.73-3.83 (4H, m), 3.99 (1H, d, J=14.4 Hz),4.06-4.18 (3H, m), 4.46-4.56 (1H, m), 6.50 (1H, s), 6.94 (1H, d, J=8.0Hz), 6.99 (2H, d, J=8.8 Hz), 7.30 (2H, d, J=8.4 Hz), 7.36-7.48 (5H, m),7.55 (1H, s), 7.79 (2H, d, J=8.4 Hz), 8.32-8.39 (1H, m).

EXAMPLE 27 Preparation of Compound 27

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.03 g) was added 1 N hydrochloricacid (8.0 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% sodium hydroxide solution (8.0ml), followed by extraction with ethyl acetate-2-propanol (4:1). Theorganic layer was washed with saturated brine and dried over magnesiumsulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline. To asolution of(2E)-3-[4′-(2-butoxyethoxy)-4-(1H-pyrazol-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylicacid (0.50 g) and DMF (0.1 ml) in THF (10 ml) was added oxalic chloride(0.094 ml) at 0° C., and the mixture was stirred at room temperature for1 hour. The solution was added dropwise to a mixture of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline and pyridine(0.96 ml) in THF (20 ml) at 0° C. After stirring the resulting mixtureat room temperature for 18 hours, water was added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith an aqueous 5% acetic acid solution, water, an aqueous sodiumhydrogen carbonate solution and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by column chromatography (basicsilica gel, ethyl acetate→ethanol:ethyl acetate 1:49) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-(1H-pyrazol-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 27) (433 mg) as a colorless amorphous material.

[α]_(D)=−136.3° (c=0.484%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.4 Hz), 0.94 (3H, t, J=7.4Hz), 1.29-1.47 (2H, m), 1.55-1.82 (4H, m), 2.11 (3H, d, J=1.4 Hz), 3.56(2H, t, J=6.6 Hz), 3.74-3.85 (4H, m), 4.02 (1H, d, J=14.2 Hz), 4.07-4.21(3H, m), 6.50 (1H, t, J=2.2 Hz), 6.58 (1H, s), 7.04 (2H, d, J=8.8 Hz),7.22-7.29 (1H, m), 7.35 (2H, d, J=8.4 Hz), 7.47-7.80 (10H, m), 7.96 (1H,s).

EXAMPLE 28 Preparation of Compound 28

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.48 g) was added 1 N hydrochloricacid (10.0 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% sodium hydroxide solution (10.0ml), followed by extraction with ethyl acetate-2-propanol (4:1). Theorganic layer was washed with saturated brine and dried over magnesiumsulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline. To asolution of(2E)-3-[6-[4-(2-butoxyethoxy)phenyl]-1-methyl-1,2,3,4-tetrahydroquinolin-8-yl]acrylicacid (0.70 g) and DMF (0.1 ml) in THF (10 ml) was added oxalic chloride(0.16 ml) at 0° C., and the mixture was stirred at room temperature for1 hour. DMF (5 ml) and THF (20 ml) were added thereto, and the solutionwas then added dropwise to a mixture of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline and pyridine(1.38 ml) in THF (20 ml) at 0° C. After stirring the resulting mixtureat room temperature for 20 hours, water was added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith an aqueous 10% acetic acid solution, water, an aqueous sodiumhydrogen carbonate solution and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by column chromatography (basicsilica gel, ethyl acetate→ethanol:ethyl acetate 1:49) to give(S)-(2E)-3-[6-[4-(2-butoxyethoxy)phenyl]-1-methyl-1,2,3,4-tetrahydroquinolin-8-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-2-acrylicamide (Compound 28) (784.5 mg) as a yellow amorphous material.

[α]_(D)=−115.4° (c=0.525%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.88 (3H, t, J=7.3 Hz), 0.94 (3H, t, J=7.2Hz), 1.29-1.49 (2H, m), 1.55-1.77 (4H, m), 1.81-1.96 (2H, m), 2.80-2.86(5H, m), 3.12-3.22 (2H, m), 3.56 (2H, t, J=6.6 Hz), 3.74-3.84 (4H, m),3.98 (1H, d, J=13.8 Hz), 4.11-4.18 (3H, m), 6.56 (1H, s), 6.63 (1H, d,J=16.5 Hz), 6.95 (2H, d, J=8.8 Hz), 7.21 (1H, d, J=2.2 Hz), 7.32 (2H, d,J=8.6 Hz), 7.40-7.48 (4H, m), 7.80 (2H, d, J=8.6 Hz), 8.05 (1H, d,J=16.5 Hz), 8.73 (1H, s).

EXAMPLE 29 Preparation of Compound 29

To (S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.23 g) was added 1 N hydrochloricacid (8.0 ml), and the mixture was extracted with ethyl acetate. To theaqueous layer was added an aqueous 25% sodium hydroxide solution (8.0ml), followed by extraction with ethyl acetate-2-propanol (4:1). Theorganic layer was washed with saturated brine and dried over magnesiumsulfate, which was concentrated under reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline. To asolution of(2E)-3-[6-[4-(2-butoxyethoxy)phenyl]-1-methyl-1,2,3,4-tetrahydroquinolin-8-yl]-2-methylacrylicacid (0.60 g) and DMF (0.1 ml) in THF (10 ml) was added oxalic chloride(0.124 ml) at 0° C., and the mixture was stirred at 0° C. for 1 hour.The solution was added dropwise to a mixture of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline and pyridine(1.15 ml) in THF (20 ml) at 0° C. After stirring the resulting mixtureat room temperature for 20 hours, water was added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith an aqueous 10% acetic acid solution, water, an aqueous sodiumhydrogen carbonate solution and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by column chromatography (basicsilica gel, ethyl acetate→ethanol:ethyl acetate 1:49) to give(S)-(2E)-3-[6-[4-(2-butoxyethoxy)phenyl]-1-methyl-1,2,3,4-tetrahydroquinolin-8-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]-2-acrylicamide (Compound 29) (461 mg) as a yellow amorphous material.

[α]_(D)=−134.2° (c=0.495%, ethanol solution)

¹H-NMR (200 MHz, CDCl₃) δ 0.91 (3H, t, J=7.4 Hz), 0.93 (3H, t, J=7.4Hz), 1.31-1.45 (2H, m), 1.56-1.89 (4H, m), 1.84-1.95 (2H, m), 2.26 (3H,d, J=1.2 Hz), 2.78 (3H, s), 2.84-2.88 (2H, m), 3.16-3.19 (2H, m), 3.55(2H, t, J=6.6 Hz), 3.75-3.82 (4H, m), 4.03 (1H, d, J=14.1 Hz), 4.07-4.17(3H, m), 6.57 (1H, s), 6.97 (2H, d, J=9.2 Hz), 7.21 (1H, d, J=1.8 Hz),7.27 (1H, d, J=1.8 Hz), 7.35 (2H, d, J=8.6 Hz), 7.42-7.45 (4H, m), 7.77(2H, d, J=8.6 Hz), 7.96 (1H, s).

EXAMPLE 30 Preparation of Compounds 30 and 31

(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 23) (570 mg) was optically resolved by using CHIRALPAK AD (50mmID×500 mL) (elusion solvent, ethanol:2-propanol=7:3). The fraction wasconcentrated into dry solid, and the residue was dissolved in ethanol,which was filtered by a 0.45 μm filter. The filtrate was concentrated togive two diastereomers of Compound 23 [the former fraction: diastereomer1 (Compound 30) (170 mg, 99.6% de) and the latter fraction: diastereomer2 (Compound 31) (173 mg, 98.0% de)].

Compound 30 [α]_(D)=−64.6° (c=0.502%, ethanol solution)

Compound 31 [α]_(D)=−197.1° (c=0.520%, ethanol solution)

EXAMPLE 31 Preparation of Compound 32

(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)anilinedi-p-toluoyl-D-tartrate monohydrate (1.01 g) was dissolved in ethylacetate (10 ml) and 1 N hydrochloric acid (5.17 ml), followed byseparation. To the aqueous layer was added an aqueous 25% potassiumcarbonate solution (5.17 ml), followed by extraction with2-propanol-ethyl acetate (1:4) twice. The organic layers were combined,washed with saturated brine and dried over magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. To the resultingresidue was added tetrahydrofuran, and then the solvent was againdistilled off under reduced pressure to give(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. To a solution of(2E)-3-[4′-(2-butoxyethoxy)-4-[(2-methoxyethyl)(methyl)amino]-1,1′-biphenyl-3-yl]acrylicacid (500 mg) in tetrahydrofuran (10 ml) was added a drop of DMF, andthen oxalyl chloride (0.133 ml) at 0° C. The mixture was returned toroom temperature and stirred for 30 minutes under a nitrogen atmosphere.The solution was then added dropwise to a solution of(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine(2.46 ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogenatmosphere. The mixture was returned to room temperature and stirred for3 hours. Then, water was added thereto and the mixture was extractedwith ethyl acetate. The organic layer was washed with an aqueous 10%acetic acid solution twice, an aqueous saturated sodium hydrogencarbonate solution twice and saturated brine once, and dried overmagnesium sulfate. The solvent was distilled off under reduced pressure,and then the resulting residue was separated and purified by basicsilica gel column chromatography (ethyl acetate→methanol:ethylacetate=3:100) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-[(2-methoxyethyl)(methyl)amino]-1,1′-biphenyl-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(527 mg) (Compound 32) as a yellow amorphous material.

¹H-NMR (300 MHz, CDCl₃) δ 0.88-0.96 (6H, m), 1.34-1.46 (2H, m),1.57-1.79 (4H, m), 2.87 (3H, s), 3.18 (2H, t, J=5.7 Hz), 3.43 (3H, s),3.56 (2H, t, J=6.9 Hz), 3.69 (2H, t, J=5.7 Hz), 3.77 (2H, t, J=7.5 Hz),3.82 (2H, t, J=4.5 Hz), 4.03 (1H, d, J=14.1 Hz), 4.11 (1H, d, J=14.1Hz), 4.17 (2H, t, J=4.5 Hz), 6.61-6.67 (2H, m), 7.00 (2H, d, J=8.7 Hz),7.18 (1H, d, J=8.4 Hz), 7.36 (2H, d, J=8.7 Hz), 7.46-7.54 (4H, m), 7.70(1H, d, J=2.1 Hz), 7.79 (2H, d, J=8.7 Hz), 8.13 (1H, d, J=16.2 Hz), 8.56(1H, s).

Elementary analysis C₃₈H₄₈N₄O₅S.0.25H₂O, Calcd. C, 67.38; H, 7.22; N,8.27. Found. C, 67.08; H, 7.62; N, 8.16.

[α]_(D)=−158.1° (C=0.322%, in ethanol)

EXAMPLE 32 Preparation of Compound 33

(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)anilinedi-p-toluoyl-D-tartrate monohydrate (636 mg) was dissolved in ethylacetate (10 ml) and 1 N hydrochloric acid (3.24 ml), followed byseparation. To the aqueous layer was added an aqueous 25% potassiumcarbonate solution (3.24 ml), followed by extraction with2-propanol-ethyl acetate (1:4). The organic layer was washed withsaturated brine, dried over magnesium sulfate, and then the solvent wasdistilled off under reduced pressure. To the resulting residue was addedtetrahydrofuran, and then the solvent was again distilled off underreduced pressure to give(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. To a solution of(2E)-3-[4′-(2-butoxyethoxy)-4-[methyl[(1-methyl-1H-pyrazol-4-yl)methyl]amino]-1,1′-biphenyl-3-yl]acrylicacid (350 mg) in dichloromethane (20 ml) was added a drop of DMF, andthen oxalyl chloride (0.083 ml) at 0° C. The mixture was returned toroom temperature and stirred for 30 minutes under a nitrogen atmosphere.The solution was then added dropwise to a solution of(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine(1.54 ml) in tetrahydrofuran (20 ml) at 0° C. under a nitrogenatmosphere. The mixture was returned to room temperature and stirred for3 hours. Then, water was added thereto and the mixture was extractedwith ethyl acetate. The organic layer was washed with an aqueous 10%acetic acid solution twice, an aqueous saturated sodium hydrogencarbonate solution twice and saturated brine once, and dried overmagnesium sulfate. The solvent was distilled off under reduced pressure,and then the resulting residue was separated and purified by basicsilica gel column chromatography (ethyl acetate→methanol:ethylacetate=1:12) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-[methyl[(1-methyl-1H-pyrazol-4-yl)methyl]amino]-1,1′-biphenyl-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(328 mg) (Compound 33) as a yellow amorphous material.

¹H-NMR (300 MHz, CDCl₃) δ 0.86-0.96 (6H, m), 1.34-1.47 (2H, m),1.58-1.78 (4H, m), 2.71 (3H, s), 3.57 (2H, t, J=6.6 Hz), 3.77-3.84 (4H,m), 3.88 (3H, s), 3.95 (2H, s), 3.99 (1H, d, J=13.8 Hz), 4.13-4.18 (3H,m), 6.54 (1H, s), 6.71 (1H, d, J=15.6 Hz), 6.98 (2H, d, J=8.4 Hz), 7.07(1H, d, J=8.4 Hz), 7.32 (2H, d, J=8.7 Hz), 7.38 (1H, s), 7.44-7.51 (5H,m), 7.66 (1H, d, J=2.1 Hz), 7.80 (2H, d, J=8.7 Hz), 8.27 (1H, d, J=15.6Hz), 8.87 (1H, s).

Elementary analysis C₄₀H₄₈N₆O₄S.0.75H₂O, Calcd. C, 66.50; H, 6.91; N,11.63. Found. C, 66.59; H, 7.02; N, 11.52.

[α]_(D)=−147.3° (C=0.398%, in ethanol)

EXAMPLE 33 Preparation of Compound 34

(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)anilinedi-p-toluoyl-D-tartrate monohydrate (424 mg) was dissolved in ethylacetate (5 ml) and 1 N hydrochloric acid (2.13 ml), followed byseparation. To the aqueous layer was added an aqueous 25% potassiumcarbonate solution (2.13 ml), followed by extraction with2-propanol-ethyl acetate (1:4) twice. The organic layers were combined,washed with saturated brine and dried over magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. To the resultingresidue was added tetrahydrofuran, and then the solvent was againdistilled off under reduced pressure to give(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. To a solution of(2E)-3-[4′-(2-butoxyethoxy)-4-[methyl[(1-methyl-1H-pyrazol-4-yl)methyl]amino]-1,1′-biphenyl-3-yl]-2-methylacrylicacid (230 mg) in dichloromethane (10 ml) was added a drop of DMF, andthen oxalyl chloride (0.055 ml) at 0° C. The mixture was returned toroom temperature and stirred for 30 minutes under a nitrogen atmosphere.The solution was then added dropwise to a solution of(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine(1.01 ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogenatmosphere. The mixture was returned to room temperature and stirred for3 hours. Then, water was added thereto and the mixture was extractedwith ethyl acetate. The organic layer was washed with an aqueous 10%acetic acid solution twice, an aqueous saturated sodium hydrogencarbonate solution twice and saturated brine once, and dried overmagnesium sulfate. The solvent was distilled off under reduced pressure,and then the resulting residue was separated and purified by basicsilica gel column chromatography (ethyl acetate→methanol:ethylacetate=1:12) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-[methyl[(1-methyl-1H-pyrazol-4-yl)methyl]amino]-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(236 mg) (Compound 34) as a yellow amorphous material.

¹H-NMR (300 MHz, CDCl₃) δ 0.89-0.96 (6H, m), 1.34-1.46 (2H, m),1.56-1.78 (4H, m), 2.29 (3H, d, J=0.9 Hz), 2.74 (3H, s), 3.56 (2H, t,J=6.9 Hz), 3.80-3.83 (7H, m), 3.96 (2H, s), 4.04 (1H, d, J=14.1 Hz),4.10 (1H, d, J=14.1 Hz), 4.17 (2H, t, J=5.4 Hz), 6.59 (1H, s), 7.01 (2H,d, J=8.7 Hz), 7.06 (1H, d, J=9.3 Hz), 7.26-7.28 (1H, m), 7.36-7.39 (3H,m), 7.47-7.50 (5H, m), 7.62 (1H, s), 7.73 (2H, d, J=8.7 Hz), 7.84 (1H,s).

Elementary analysis C₄₁H₅₀N₆O₄S.0.5H₂O, Calcd. C, 67.28; H, 7.02; N,11.48. Found. C, 66.97; H, 6.97; N, 11.37.

[α]_(D)=−126.7° (C=0.357%, in ethanol)

EXAMPLE 34 Preparation of Compound 35

(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)anilinedi-p-toluoyl-D-tartrate monohydrate (256 mg) was dissolved in ethylacetate (5 ml) and 1 N hydrochloric acid (2.6 ml), followed byseparation. To the aqueous layer was added an aqueous 25% potassiumcarbonate solution (2.6 ml), followed by extraction with2-propanol-ethyl acetate (1:4) twice. The organic layers were combined,washed with saturated brine and dried over magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. To the resultingresidue was added tetrahydrofuran, and then the solvent was againdistilled off under reduced pressure to give(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. To a solution of(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]but-2-enoicacid (125 mg) in tetrahydrofuran (10 ml) was added a drop of DMF, andthen oxalyl chloride (0.034 ml) at 0° C. The mixture was returned toroom temperature and stirred for 30 minutes under a nitrogen atmosphere.The solution was then added dropwise to a solution of(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine(0.62 ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogenatmosphere. The mixture was returned to room temperature and stirred for3 hours. Then, water was added thereto and the mixture was extractedwith ethyl acetate. The organic layer was washed with an aqueous 10%acetic acid solution twice, an aqueous saturated sodium hydrogencarbonate solution twice and saturated brine once, and dried overmagnesium sulfate. The solvent was distilled off under reduced pressure,and then the resulting residue was separated and purified by basicsilica gel column chromatography (hexane:ethyl acetate=1:1→ethylacetate) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]but-2-enoicamide (41 mg) (Compound 35) as a yellow amorphous material.

¹H-NMR (300 MHz, CDCl₃) δ 0.87-0.95 (6H, m), 1.35-1.43 (2H, m),1.55-1.75 (4H, m), 1.88-1.95 (4H, m), 2.60 (3H, s), 3.20-3.30 (4H, m),3.55 (2H, t, J=6.3 Hz), 3.75-3.82 (4H, m), 3.99 (1H, d, J=13.8 Hz),4.07-4.16 (3H, m), 6.02 (1H, s), 6.53 (1H, s), 6.87 (1H, d, J=8.4 Hz),6.96 (2H, d, J=9.0 Hz), 7.24-7.47 (7H, m), 7.74 (2H, d, J=8.7 Hz), 7.86(1H, s).

Elementary analysis C₃₉H₄₈N₄O₄S.0.5H₂O, Calcd. C, 69.10; H, 7.29; N,8.26. Found. C, 69.20; H, 7.37; N, 8.33.

[α]_(D)=−144.7° (C=0.301%, in ethanol)

EXAMPLE 35 Preparation of Compound 36

(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)anilinedi-p-toluoyl-D-tartrate monohydrate (371 mg) was dissolved in ethylacetate (5 ml) and 1 N hydrochloric acid (2.8 ml), followed byseparation. To the aqueous layer was added an aqueous 25% potassiumcarbonate solution (2.8 ml), followed by extraction with2-propanol-ethyl acetate (1:4) twice. The organic layers were combined,washed with saturated brine and dried over magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. To the resultingresidue was added tetrahydrofuran, and then the solvent was againdistilled off under reduced pressure to give(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. To a solution of(2E)-3-[4′-(2-butoxyethoxy)-4-(2,5-dihydro-1H-pyrrol-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylicacid (180 mg) in tetrahydrofuran (10 ml) was added a drop of DMF, andthen oxalyl chloride (0.048 ml) at 0° C. The mixture was returned toroom temperature and stirred for 30 minutes under a nitrogen atmosphere.The solution was then added dropwise to a solution of(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine (0.9ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogen atmosphere. Themixture was returned to room temperature and stirred for 3 hours. Then,water was added thereto and the mixture was extracted with ethylacetate. The organic layer was washed with an aqueous 10% acetic acidsolution twice, an aqueous saturated sodium hydrogen carbonate solutiontwice and saturated brine once, and dried over magnesium sulfate. Thesolvent was distilled off under reduced pressure, and then the resultingresidue was separated and purified by basic silica gel columnchromatography (ethyl acetate→methanol:ethyl acetate=1:25) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-(1H-pyrrol-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(107 mg) (Compound 36) as a yellow amorphous material.

¹H-NMR (300 MHz, CDCl₃) δ 0.89-0.96 (6H, m), 1.35-1.50 (2H, m),1.55-1.80 (4H, m), 2.16 (3H, s), 3.56 (2H, t, J=6.3 Hz), 3.76-3.84 (4H,m), 4.00-4.20 (4H, m), 6.36-6.40 (2H, m), 6.57 (1H, s), 6.85-6.91 (3H,m), 7.04 (2H, d, J=8.7 Hz), 7.35 (2H, d, J=9.0 Hz), 7.43-7.69 (9H, m).

Elementary analysis C₃₉H₄₄N₄O₄S.0.5H₂O, Calcd. C, 69.51; H, 6.73; N,8.31. Found. C, 69.38; H, 6.72; N, 8.06.

[α]_(D)=−130.1° (C=0.244%, in ethanol)

EXAMPLE 36 Preparation of Compound 37

(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)anilinedi-p-toluoyl-D-tartrate monohydrate (721 mg) was dissolved in ethylacetate (10 ml) and 1 N hydrochloric acid (5.4 ml), followed byseparation. To the aqueous layer was added an aqueous 25% potassiumcarbonate solution (5.4 ml), followed by extraction with2-propanol-ethyl acetate (1:4) twice. The organic layers were combined,washed with saturated brine and dried over magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. To the resultingresidue was added tetrahydrofuran, and then the solvent was againdistilled off under reduced pressure to give(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. To a solution of(2E)-3-[4′-(2-butoxyethoxy)-4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-1,1′-biphenyl-3-yl]-2-methylacrylicacid (400 mg) in tetrahydrofuran (10 ml) was added a drop of DMF, andthen oxalyl chloride (0.094 ml) at 0° C. The mixture was returned toroom temperature and stirred for 30 minutes under a nitrogen atmosphere.The solution was then added dropwise to a solution of(S)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine(1.75 ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogenatmosphere. The mixture was returned to room temperature and stirred for3 hours. Then, water was added thereto and the mixture was extractedwith ethyl acetate. The organic layer was washed with water twice andsaturated brine once, and then dried over magnesium sulfate. The solventwas distilled off under reduced pressure, which was separated andpurified by basic silica gel column chromatography (ethylacetate→methanol:ethyl acetate=1:50). The resulting residue wasrecrystallized from diisopropyl ether-ethyl acetate to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(319 mg) (Compound 37) as yellow crystals.

m.p. 139.5-140.5° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.89-0.96 (6H, m), 1.33-1.46 (2H, m),1.56-1.77 (4H, m), 2.18-2.23 (5H, m), 3.26 (2H, s), 3.38 (2H, t, J=6.6Hz), 3.55 (2H, t, J=6.6 Hz), 3.75-3.82 (4H, m), 3.89-4.18 (8H, m), 6.62(1H, s), 6.94-7.00 (3H, m), 7.37-7.51 (8H, m), 7.81 (2H, d, J=8.7 Hz),8.00 (1H, s).

Elementary analysis C₄₁H₅₀N₄O₆S, Calcd. C, 67.74; H, 6.93; N, 7.71.Found. C, 67.48; H, 7.17; N, 7.57.

[α]_(D)=−128.4° (C=0.465%, in ethanol)

EXAMPLE 37 Preparation of Compound 38

(−)-4-(((1-Propylimidazol-5-yl)methyl)sulfinyl)anilinedi-p-toluoyl-D-tartrate monohydrate (473 mg) was dissolved in ethylacetate (10 ml) and 1 N hydrochloric acid (3.54 ml), followed byseparation. To the aqueous layer was added an aqueous 25% potassiumcarbonate solution (3.54 ml), followed by extraction with2-propanol-ethyl acetate (1:4) twice. The organic layers were combined,washed with saturated brine and dried over magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. To the resultingresidue was added tetrahydrofuran, and then the solvent was againdistilled off under reduced pressure to give(−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. To a solution of(2E)-3-[4-[3-[(acetyloxy)methyl]pyrrolidin-1-yl]-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]-2-methylacrylicacid (270 mg) in tetrahydrofuran (10 ml) was added a drop of DMF, andthen oxalyl chloride (0.062 ml) at 0° C. The mixture was returned toroom temperature and stirred for 30 minutes under a nitrogen atmosphere.The solution was then added dropwise to a solution of(−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine(1.15 ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogenatmosphere. The mixture was returned to room temperature and stirredovernight. Then, water was added thereto and the mixture was extractedwith ethyl acetate. The organic layer was washed with water twice andsaturated brine once, and then dried over magnesium sulfate. The solventwas distilled off under reduced pressure, and then the resulting residuewas separated and purified by basic silica gel column chromatography(ethyl acetate→methanol:ethyl acetate=1:25) to give(Ss)-(2E)-3-[4-[3-(acetoxymethyl)pyrrolidin-1-yl]-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(222 mg) (Compound 38) as a yellow amorphous material.

¹H-NMR (300 MHz, CDCl₃) δ 0.90-0.96 (6H, m), 1.36-1.43 (2H, m),1.50-1.78 (5H, m), 2.05-2.19 (7H, m), 2.55-2.70 (1H, m), 3.09-3.15 (1H,m), 3.29-3.35 (3H, m), 3.55 (2H, t, J=6.6 Hz), 3.78-3.83 (4H, m),4.02-4.18 (6H, m), 6.58 (1H, s), 6.92 (1H, d, J=9.0 Hz), 6.99 (2H, d,J=9.0 Hz), 7.35-7.47 (7H, m), 7.59 (1H, s), 7.77-7.80 (3H, m).

Elementary analysis C₄₂H₅₂N₄O₆S.0.5H₂O, Calcd. C, 67.26; H, 7.12; N,7.47. Found. C, 67.01; H, 7.06; N, 7.28.

[α]_(D)=−118.2° (C=0.350%, in ethanol)

EXAMPLE 38 Preparation of Compound 39

To a solution of(Ss)-(2E)-3-[4-[3-(acetoxymethyl)pyrrolidin-1-yl]-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 38) (150 mg) in tetrahydrofuran (3 ml) and methanol (3 ml) wasadded a 1 N aqueous sodium hydroxide solution (0.3 ml), and the mixturewas stirred at room temperature for 3 hours. To the reaction solutionwas added water, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over magnesiumsulfate. The solvent was distilled off under reduced pressure, and thenthe resulting residue was separated and purified by basic silica gelcolumn chromatography (ethyl acetate→methanol:ethyl acetate=1:19) togive(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-[3-(hydroxymethyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(91.8 mg) (Compound 39) as a yellow amorphous material.

¹H-NMR (300 MHz, CDCl₃) δ 0.89-0.96 (6H, m), 1.36-1.46 (2H, m),1.50-1.85 (5H, m), 2.10-2.25 (4H, m), 2.45-2.55 (1H, m), 2.83-2.90 (1H,m), 3.15-3.30 (2H, m), 3.48-3.57 (3H, m), 3.75-3.82 (6H, m), 3.98-4.17(4H, m), 6.51 (1H, d, J=6.3 Hz), 6.97-7.03 (3H, m), 7.31-7.35 (2H, m),7.41-7.47 (6H, m), 7.82 (2H, d, J=8.1 Hz), 8.78 (1H, d, J=3.9 Hz).

Elementary analysis C₄₀H₅₀N₄O₅S 0.5H₂O, Calcd. C, 67.87; H, 7.26; N,7.91. Found. C, 67.58; H, 7.24; N, 7.88.

[α]_(D)=−125.9° (C=0.370%, in ethanol)

EXAMPLE 39 Preparation of Compound 40

(−)-4-(((1-Propylimidazol-5-yl)methyl)sulfinyl)anilinedi-p-toluoyl-D-tartrate monohydrate (423 mg) was dissolved in ethylacetate (10 ml) and 1 N hydrochloric acid (3.17 ml), followed byseparation. To the aqueous layer was added an aqueous 25% potassiumcarbonate solution (3.17 ml), followed by extraction with2-propanol-ethyl acetate (1:4) twice. The organic layers were combined,washed with saturated brine and dried over magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. To the resultingresidue was added tetrahydrofuran, and then the solvent was againdistilled off under reduced pressure to give(−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. To a solution of(2E)-3-[4′-(2-butoxyethoxy)-4-[3-(methoxycarbonyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methylacrylicacid (235 mg) in tetrahydrofuran (10 ml) was added a drop of DMF, andthen oxalyl chloride (0.055 ml) at 0° C. The mixture was returned toroom temperature and stirred for 30 minutes under a nitrogen atmosphere.The solution was then added dropwise to a solution of(−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine(1.03 ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogenatmosphere. The mixture was returned to room temperature and stirredovernight. Then, water was added thereto and the mixture was extractedwith ethyl acetate. The organic layer was washed with water twice andsaturated brine once, and then dried over magnesium sulfate. The solventwas distilled off under reduced pressure, and then the resulting residuewas separated and purified by basic silica gel column chromatography(ethyl acetate→methanol:ethyl acetate=1:20) to give(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-[3-(methoxycarbonyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(38 mg) (Compound 40) as a yellow amorphous material.

¹H-NMR (300 MHz, CDCl₃) δ 0.88-0.96 (6H, m), 1.35-1.47 (2H, m),1.50-1.80 (4H, m), 2010-2.25 (4H, m), 2.30-2.50 (1H, m), 2.77-2.83 (1H,m), 3.10-3.35 (3H, m), 3.56 (2H, t, J=6.6 Hz), 3.70-3.77 (5H, m), 3.81(2H, t, J=4.8 Hz), 3.95-4.18 (5H, m), 6.66 (1H, s), 6.97-7.01 (3H, m),7.37 (2H, d, J=7.8 Hz), 7.44-7.49 (6H, m), 7.98-8.02 (2H, m), 9.04 (1H,s).

Elementary analysis C₄₁H₅₀N₄O₆S.0.5H₂O, Calcd. C, 66.91; H, 6.98; N,7.61. Found. C, 66.83; H, 6.99; N, 7.44.

[α]_(D)=−123.6° (C=0.223%, in ethanol)

EXAMPLE 40 Preparation of Compound 41

To a solution of(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-[3-(methoxycarbonyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 40) (220 mg) in tetrahydrofuran (6 ml) and methanol (6 ml) wasadded a 1 N aqueous sodium hydroxide solution (0.12 ml), and the mixturewas stirred at room temperature for 7 hours. To the reaction solutionwere added water and 1 N hydrochloric acid (0.9 ml), and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue wasseparated and purified by preparative HPLC to give(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-carboxypyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(117 mg) (Compound 41) as a yellow amorphous material.

m.p. 184.0-186.0° C.

Elementary analysis C₄₀H₄₈N₄O₆S.0.5H₂O, Calcd. C, 66.55; H, 6.84; N,7.76. Found. C, 66.68; H, 6.76; N, 7.49.

[α]_(D)=−155.0° (C=0.324%, in ethanol)

EXAMPLE 41 Preparation of Compound 42

(−)-4-(((1-Propylimidazol-5-yl)methyl)sulfinyl)anilinedi-p-toluoyl-D-tartrate monohydrate (768 mg) was dissolved in ethylacetate (10 ml) and 1 N hydrochloric acid (5.75 ml), followed byseparation. To the aqueous layer was added an aqueous 25% potassiumcarbonate solution (5.75 ml), followed by extraction with2-propanol-ethyl acetate (1:4) twice. The organic layers were combined,washed with saturated brine and dried over magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. To the resultingresidue was added tetrahydrofuran, and then the solvent was againdistilled off under reduced pressure to give(−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. To a solution of(2E)-3-[4′-(2-butoxyethoxy)-4-(3,4-dimethylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylicacid (400 mg) in tetrahydrofuran (10 ml) was added a drop of DMF, andthen oxalyl chloride (0.1 ml) at 0° C. The mixture was returned to roomtemperature and stirred for 30 minutes under a nitrogen atmosphere. Thesolution was then added dropwise to a solution of(−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine(1.86 ml) in tetrahydrofuran (15 ml) at 0° C. under a nitrogenatmosphere. The mixture was returned to room temperature and stirredovernight. Then, water was added thereto and the mixture was extractedwith ethyl acetate. The organic layer was washed with water twice andsaturated brine once, and then dried over magnesium sulfate. The solventwas distilled off under reduced pressure, and then the resulting residuewas separated and purified by basic silica gel column chromatography(ethyl acetate→methanol:ethyl acetate 1:20) to give(S)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3,4-dimethylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(316 mg) (Compound 42) as a yellow amorphous material.

¹H-NMR (300 MHz, CDCl₃) δ 0.89-0.98 (12H, m), 1.35-1.45 (2H, m),1.50-1.65 (2H, m), 1.70-1.78 (2H, m), 2.16 (3H, d, J=1.2 Hz), 2.22-2.37(2H, m), 2.99-3.04 (2H, m), 3.41-3.46 (2H, m), 3.54 (2H, t, J=6.6 Hz),3.77-3.81 (4H, m), 4.03 (1H, d, J=14.1 Hz), 4.07-4.16 (3H, m), 6.56 (1H,s), 6.83 (1H, d, J=8.7 Hz), 6.96 (2H, d, J=8.7 Hz), 7.30 (1H, d, J=1.8Hz), 7.35-7.45 (6H, m), 7.64 (1H, s), 7.75-7.79 (3H, m).

Elementary analysis C₄₁H₅₂N₄O₄S.0.5H₂O, Calcd. C, 69.76; H, 7.57; N,7.94. Found. C, 69.62; H, 7.47; N, 7.69.

[α]_(D)=−126.6° (C=0.374%, in ethanol)

EXAMPLE 42 Preparation of Compound 43

To a solution of(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-carboxypyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 41) (120 mg), ammonium chloride (11.2 mg) and1-hydroxybenzotriazole monohydrate (33.4 mg) in DMF (5 ml) were addedtriethylamine (0.03 ml) and a catalytic amount of4-(N,N-dimethylamino)pyridine, followed by adding1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (41.8 mg),and the mixture was stirred overnight under a nitrogen atmosphere. Waterwas added thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over magnesiumsulfate. The solvent was distilled off under reduced pressure, and thenthe resulting residue was purified by silica gel column chromatography(ethyl acetate→methanol:ethyl acetate=1:11) to give(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-carbamoylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 43) (32.4 mg) as a yellow amorphous material.

¹H-NMR (300 MHz, CDCl₃) δ 0.87-0.96 (6H, m), 1.33-1.46 (2H, m),1.56-1.90 (4H, m), 2.10-2.30 (4H, m), 2.35-2.45 (1H, m), 2.71 (1H, t,J=8.1 Hz), 2.95-3.07 (1H, m), 3.11-3.20 (1H, m), 3.32-3.37 (1H, m), 3.55(2H, t, J=6.9 Hz), 3.73-3.83 (4H, m), 3.93-4.18 (5H, m), 5.78 (1H, br),5.97-6.09 (1H, m), 6.50 (1H, d, J=17.1 Hz), 6.96-7.01 (3H, m), 7.26-7.32(2H, m), 7.41-7.48 (6H, m), 6.69 (2H, d, J=7.5 Hz), 9.45 (1H, s).

Elementary analysis C₄₀H₄₉NO₅S.1.0H₂O, Calcd. C, 65.82; H, 7.04; N,9.59. Found. C, 65.82; H, 7.01; N, 9.28.

[α]_(D)=−122.8° (C=0.247%, in ethanol)

EXAMPLE 43 Preparation of Compound 44

To a solution of(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-[3-carboxypyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 41) (120 mg), methylammonium chloride (14.2 mg) and1-hydroxybenzotriazole monohydrate (33.4 mg) in DMF (5 ml) were addedtriethylamine (0.03 ml) and a catalytic amount of4-(N,N-dimethylamino)pyridine, followed by adding1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (41.8 mg),and the mixture was stirred overnight under a nitrogen atmosphere. Waterwas added thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over magnesiumsulfate. The solvent was distilled off under reduced pressure, and thenthe resulting residue was purified by silica gel column chromatography(ethyl acetate→methanol:ethyl acetate=1:11) and recrystallized fromethyl acetate-diisopropyl ether to give(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-[3-(methylaminocarbonyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 44) (65.2 mg) as yellow crystals.

m.p. 127.0-128.5° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.87-0.96 (6H, m), 1.36-1.43 (2H, m),1.50-1.74 (4H, m), 2.05-2.25 (4H, m), 2.30-2.45 (1H, m), 2.60-2.70 (1H,m), 2.85-3.00 (4H, m), 3.05-3.20 (1H, m), 3.30-3.40 (1H, m), 3.55 (2H,t, J=6.6 Hz), 3.65-3.75 (2H, m), 3.81 (2H, t, J=4.2 Hz), 4.00-4.18 (5H,m), 5.60-5.70 (1H, m), 6.71 (1H, s), 6.98-7.01 (3H, m), 7.35-7.38 (2H,m), 7.46-7.49 (6H, m), 8.14-8.19 (2H, m), 9.70 (1H, s).

Elementary analysis C₄₁H₅₁N₅O₅S.0.5H₂O, Calcd. C, 67.00; H, 7.13; N,9.53. Found. C, 66.78; H, 7.06; N, 9.25.

[α]_(D)=−124.7° (C=0.322%, in ethanol)

EXAMPLE 44 Preparation of Compound 45

To a solution of(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-[3-carboxypyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 41) (120 mg), dimethylammonium chloride (17.1 mg) and1-hydroxybenzotriazole monohydrate (33.4 mg) in DMF (5 ml) were addedtriethylamine (0.03 ml) and a catalytic amount of4-(N,N-dimethylamino)pyridine, followed by adding1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (41.8 mg),and the mixture was stirred overnight under a nitrogen atmosphere. Waterwas added thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over magnesiumsulfate. The solvent was distilled off under reduced pressure, and thenthe resulting residue was purified by silica gel column chromatography(ethyl acetate→methanol:ethyl acetate=1:11) and recrystallized fromethyl acetate-diisopropyl ether to give(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-[3-(dimethylaminocarbonyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 45) (76.5 mg) as yellow crystals.

m.p. 151.0-152.0° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.86-0.96 (6H, m), 1.36-1.73 (6H, m),1.90-2.05 (1H, m), 2.25 (3H, s), 2.45-2.60 (2H, m), 2.95-3.20 (7H, m),3.22-3.40 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.62-3.70 (2H, m), 3.81 (2H,t, J=4.5 Hz), 4.00-4.29 (5H, m), 6.74 (1H, d, J=4.8 Hz), 6.96-7.01 (3H,m), 7.33-7.37 (2H, m), 7.44-7.54 (6H, m), 8.13-8.19 (2H, m), 10.09 (1H,s).

Elementary analysis C₄₂H₅₃N₅O₅S.0.75H₂O, Calcd. C, 66.95; H, 7.29; N,9.29. Found. C, 66.96; H, 7.13; N, 9.32.

[α]_(D)=−117.7° (C=0.331%, in ethanol)

EXAMPLE 45 Preparation of Compound 46

(−)-4-(((1-Propylimidazol-5-yl)methyl)sulfinyl)anilinedi-p-toluoyl-D-tartrate monohydrate (360 mg) was dissolved in ethylacetate (5 ml) and 1 N hydrochloric acid (2.7 ml), followed byseparation. To the aqueous layer was added an aqueous 25% potassiumcarbonate solution (2.7 ml), followed by extraction with2-propanol-ethyl acetate (1:4) twice. The organic layers were combined,washed with saturated brine and dried over magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. To the resultingresidue was added tetrahydrofuran, and then the solvent was againdistilled off under reduced pressure to give(−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. To a solution of(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-pyrrolidin-1-ylpyridin-3-yl]acrylicacid (170 mg) in dichloromethane (10 ml) was added a drop of DMF, andthen oxalyl chloride (0.047 ml) at 0° C. The mixture was returned toroom temperature and stirred for 30 minutes under a nitrogen atmosphere.The solution was then added dropwise to a solution of(−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine(0.87 ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogenatmosphere. The mixture was returned to room temperature and stirred for3 hours. Then, water was added thereto and the mixture was extractedwith ethyl acetate. The organic layer was washed with water twice andsaturated brine once, and then dried over magnesium sulfate. The solventwas distilled off under reduced pressure, and then the resulting residuewas separated and purified by basic silica gel column chromatography(ethyl acetate→methanol:ethyl acetate=3:100) to give(S)-(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-pyrrolidin-1-ylpyridin-3-yl]-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(131 mg) (Compound 46) as a yellow amorphous material.

¹H-NMR (200 MHz, CDCl₃) δ 0.87-0.96 (6H, m), 1.34-1.44 (2H, m),1.50-1.80 (4H, m), 1.90-1.96 (4H, m), 3.56 (2H, t, J=6.9 Hz), 3.60-3.68(4H, m), 3.78-3.83 (4H, m), 3.98 (1H, d, J=14.1 Hz), 4.13-4.18 (3H, m),6.40 (1H, d, J=15.0 Hz), 6.51 (1H, s), 6.98 (2H, d, J=8.7 Hz), 7.32 (2H,d, J=9.0 Hz), 7.40 (2H, d, J=8.7 Hz), 7.48 (1H, s), 7.71 (1H, d, J=2.4Hz), 7.78 (2H, d, J=9.0 Hz), 8.11 (2H, d, J=15.0 Hz), 8.36 (1H, d, J=2.4Hz), 8.59 (1H, s).

Elementary analysis C₃₇H₄₅N₅O₄S.0.5H₂O, Calcd. C, 66.84; H, 6.97; N,10.53. Found. C, 66.72; H, 6.96; N, 10.24.

[α]_(D)=−166.5° (C=0.327%, in ethanol)

EXAMPLE 46 Preparation of Compound 47

(−)-4-(((1-Propylimidazol-5-yl)methyl)sulfinyl)anilinedi-p-toluoyl-D-tartrate monohydrate (327 mg) was dissolved in ethylacetate (5 ml) and 1 N hydrochloric acid (2.45 ml), followed byseparation. To the aqueous layer was added an aqueous 25% potassiumcarbonate solution (2.45 ml), followed by extraction with2-propanol-ethyl acetate (1:4) twice. The organic layers were combined,washed with saturated brine and dried over magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. To the resultingresidue was added tetrahydrofuran, and then the solvent was againdistilled off under reduced pressure to give(−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. To a solution of(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-pyrrolidin-1-ylpyridin-3-yl]-2-methylacrylicacid (160 mg) in dichloromethane (10 ml) was added a drop of DMF, andthen oxalyl chloride (0.043 ml) at 0° C. The mixture was returned toroom temperature and stirred for 30 minutes under a nitrogen atmosphere.The solution was then added dropwise to a solution of(−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine(0.79 ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogenatmosphere. The mixture was returned to room temperature and stirred for3 hours. Then, water was added thereto and the mixture was extractedwith ethyl acetate. The organic layer was washed with water twice andsaturated brine once, and then dried over magnesium sulfate. The solventwas distilled off under reduced pressure, and then the resulting residuewas separated and purified by basic silica gel column chromatography(ethyl acetate→methanol:ethyl acetate=1:100) to give(S)-(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-pyrrolidin-1-ylpyridin-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(156 mg) (Compound 47) as a yellow amorphous material.

¹H-NMR (200 MHz, CDCl₃) δ 0.91-0.96 (6H, m), 1.36-1.43 (2H, m),1.52-1.66 (2H, m), 1.72-1.79 (2H, m), 1.90-2.00 (4H, m), 2.13 (3H, s),3.50-3.57 (6H, m), 3.79-3.85 (4H, m), 4.03 (1H, d, J=14.4 Hz), 4.09-4.18(3H, m), 6.53 (1H, s), 7.00 (2H, d, J=8.7 Hz), 7.35-7.47 (5H, m), 7.50(1H, d, J=2.4 Hz), 7.64 (1H, s), 7.76-7.79 (3H, m), 8.36 (1H, d, J=2.4Hz).

Elementary analysis C₃₈H₄₇N₅O₄S.0.5H₂O, Calcd. C, 67.23; H, 7.13; N,10.32. Found. C, 67.11; H, 7.05; N, 10.08.

[α]_(D)=−134.8° (C=0.407%, in ethanol)

EXAMPLE 47 Preparation of Compound 48

(−)-4-(((1-Propylimidazol-5-yl)methyl)sulfinyl)anilinedi-p-toluoyl-D-tartrate monohydrate (988 mg) was dissolved in ethylacetate (7 ml) and 1 N hydrochloric acid (5.03 ml), followed byseparation. To the aqueous layer was added an aqueous 25% potassiumcarbonate solution (5.03 ml), followed by extraction with2-propanol-ethyl acetate (1:4) twice. The organic layers were combined,washed with saturated brine and dried over magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. To the resultingresidue was added tetrahydrofuran, and then the solvent was againdistilled off under reduced pressure to give(−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. To a solution of(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-(3-methylpyrrolidin-1-yl)pyridin-3-yl]-2-methylacrylicacid (500 mg) in dichloromethane (10 ml) was added a drop of DMF, andthen oxalyl chloride (0.13 ml) at 0° C. The mixture was returned to roomtemperature and stirred for 30 minutes under a nitrogen atmosphere. Thesolution was then added dropwise to a solution of(−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine (2.4ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogen atmosphere. Themixture was returned to room temperature and stirred for 3 hours. Then,water was added thereto and the mixture was extracted with ethylacetate. The organic layer was washed with water twice and saturatedbrine once, and then dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue wasseparated and purified by basic silica gel column chromatography (ethylacetate→methanol:ethyl acetate 3:100) to give(Ss)-(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-(3-methylpyrrolidin-1-yl)pyridin-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(660 mg) (Compound 48) as a yellow amorphous material.

¹H-NMR (200 MHz, CDCl₃) δ 0.90-0.95 (6H, m), 1.10 (3H, d, J=6.6 Hz),1.36-1.43 (2H, m), 1.50-1.78 (5H, m), 2.00-2.11 (1H, m), 2.13 (3H, d,J=1.2 Hz), 2.20-2.40 (1H, m), 3.11-3.18 (1H, m), 3.48-3.66 (5H, m),3.78-3.84 (4H, m), 4.02 (1H, d, J=14.1 Hz), 4.09-4.17 (3H, m), 6.52 (1H,s), 6.99 (2H, d, J=9.0 Hz), 7.34-7.48 (6H, m), 7.62 (1H, s), 7.75-7.80(3H, m), 8.34 (1H, d, J=2.4 Hz).

Elementary analysis C₃₉H₄₉N₅O₄S.0.5H₂O, Calcd. C, 67.60; H, 7.27; N,10.11. Found. C, 67.50; H, 7.18; N, 9.88.

[α]_(D)=−135.6° (C=0.333%, in ethanol)

EXAMPLE 48 Preparation of Compound 49

(−)-4-(((1-Propylimidazol-5-yl)methyl)sulfinyl)anilinedi-p-toluoyl-D-tartrate monohydrate (701 mg) was dissolved in ethylacetate (10 ml) and 1 N hydrochloric acid (3.6 ml), followed byseparation. To the aqueous layer was added an aqueous 25% potassiumcarbonate solution (3.6 ml), followed by extraction with2-propanol-ethyl acetate (1:4) twice. The organic layers were combined,washed with saturated brine and dried over magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. To the resultingresidue was added tetrahydrofuran, and then the solvent was againdistilled off under reduced pressure to give(−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. To a solution of(2E)-3-[2-(3-acetoxymethyl)pyrrolidin-1-yl]-5-[4-(2-butoxyethoxy)phenyl]pyridin-3-yl]-2-methylacrylicacid (400 mg) in dichloromethane (10 ml) was added a drop of DMF, andthen oxalyl chloride (0.092 ml) at 0° C. The mixture was returned toroom temperature and stirred for 30 minutes under a nitrogen atmosphere.The solution was then added dropwise to a solution of(−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine(2.08 ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogenatmosphere. The mixture was returned to room temperature and stirred for3 hours. Then, water was added thereto and the mixture was extractedwith ethyl acetate. The organic layer was washed with water twice andsaturated brine once, and then dried over magnesium sulfate. The solventwas distilled off under reduced pressure, and then the resulting residuewas separated and purified by basic silica gel column chromatography(ethyl acetate→methanol:ethyl acetate=1:19) to give(Ss)-(2E)-3-[2-[3-(acetoxymethyl)pyrrolidin-1-yl]-5-[4-(2-butoxyethoxy)phenyl]pyridin-3-yl]-2-methyl-N-(4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(458 mg) (Compound 49) as a yellow amorphous material.

¹H-NMR (200 MHz, CDCl₃) δ 0.90-0.96 (6H, m), 1.33-1.43 (2H, m),1.55-1.79 (5H, m), 1.95-2.13 (7H, m), 2.55-2.65 (1H, m), 3.37-3.43 (1H,m), 3.53-3.59 (4H, m), 3.63-3.69 (1H, m), 3.79-3.85 (4H, m), 4.01-4.18(6H, m), 6.53 (1H, s), 7.00 (2H, d, J=8.7 Hz), 7.36-7.47 (5H, m), 7.52(1H, d, J=1.8 Hz), 7.60 (1H, s), 7.79 (2H, d, J=8.7 Hz), 7.85 (1H, s),8.36 (1H, d, J=2.4 Hz).

Elementary analysis C₄₁H₅₁N₅O₆S.0.5H₂O, Calcd. C, 65.58; H, 6.98; N,9.33. Found. C, 65.59; H, 7.01; N, 9.03.

[α]_(D)=−119.8° (C=0.408%, in ethanol)

EXAMPLE 49 Preparation of Compound 50

To a solution of(Ss)-(2E)-3-[2-[3-(acetoxymethyl)pyrrolidin-1-yl]-5-[4-(2-butoxyethoxy)phenyl]pyridin-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 49) (220 mg) in tetrahydrofuran (4 ml) and methanol (4 ml) wasadded a 1 N aqueous sodium hydroxide solution (0.445 ml), and themixture was stirred at room temperature for 3.5 hours. To the reactionsolution were added water and 1 N hydrochloric acid (0.4 ml), and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue wasseparated and purified by silica gel column chromatography (ethylacetate→methanol:ethyl acetate=1:9) to give(Ss)-(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-[3-(hydroxymethyl)pyrrolidin-1-yl]pyridin-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(150 mg) (Compound 50) as a yellow amorphous material.

¹H-NMR (200 MHz, CDCl₃) δ 0.88-0.96 (6H, m), 1.33-1.46 (2H, m),1.50-1.79 (5H, m), 2.05-2.16 (4H, m), 2.45-2.55 (1H, m), 3.35-3.50 (1H,m), 3.53-3.58 (4H, m), 3.67-3.71 (1H, m), 3.79-4.18 (10H, m), 6.41 (1H,d, J=4.8 Hz), 7.00 (2H, d, J=9.0 Hz), 7.28-7.46 (6H, m), 7.52 (1H, d,J=2.4 Hz), 7.80 (2H, dd, J=8.7, 1.8 Hz), 8.26 (1H, d, J=3.9 Hz), 8.36(1H, d, J=2.7 Hz).

Elementary analysis C₃₉H₄₉N₅O₅S.0.75H₂O, Calcd. C, 65.66; H, 7.13; N,9.82. Found. C, 65.60; H, 7.08; N, 9.54.

[α]_(D)=−128.6° (C=0.436%, in ethanol)

EXAMPLE 50 Preparation of Compound 51

(−)-4-(((1-Propylimidazol-5-yl)methyl)sulfinyl)anilinedi-p-toluoyl-D-tartrate monohydrate (409 mg) was dissolved in ethylacetate (5 ml) and 1 N hydrochloric acid (2.1 ml), followed byseparation. To the aqueous layer was added an aqueous 25% potassiumcarbonate solution (2.1 ml), followed by extraction with2-propanol-ethyl acetate (1:4) twice. The organic layers were combined,washed with saturated brine and dried over magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. To the resultingresidue was added tetrahydrofuran, and then the solvent was againdistilled off under reduced pressure to give(−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline. To a solution of(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-(3,4-dimethylpyrrolidin-1-yl)pyridin-3-yl]-2-methylacrylicacid (220 mg) in dichloromethane (10 ml) was added a drop of DMF, andthen oxalyl chloride (0.053 ml) at 0° C. The mixture was returned toroom temperature and stirred for 30 minutes under a nitrogen atmosphere.The solution was then added dropwise to a solution of(−)-4-(((1-propylimidazol-5-yl)methyl)sulfinyl)aniline and pyridine(0.99 ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogenatmosphere. The mixture was returned to room temperature and stirred for3 hours. Then, water was added thereto and the mixture was extractedwith ethyl acetate. The organic layer was washed with water twice andsaturated brine once, and then dried over magnesium sulfate. The solventwas distilled off under reduced pressure, and then the resulting residuewas separated and purified by basic silica gel column chromatography(hexane:ethyl acetate=1:1→ethyl acetate) to give(S)-(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-(3,4-dimethylpyrrolidin-1-yl)pyridin-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(220 mg) (Compound 51) as a yellow amorphous material.

¹H-NMR (200 MHz, CDCl₃) δ 0.90-0.98 (12H, m), 1.36-1.46 (2H, m),1.56-1.80 (4H, m), 2.12 (3H, s), 2.20-2.40 (2H, m), 3.22-3.27 (2H, m),3.55 (2H, t, J=6.6 Hz), 3.58-3.65 (2H, m), 3.79-3.85 (4H, m), 4.03 (1H,d, J=14.1 Hz), 4.09-4.17 (3H, m), 6.53 (1H, s), 6.99 (2H, d, J=8.7 Hz),7.35-7.52 (6H, m), 7.64 (1H, s), 7.77-7.81 (3H, m), 8.39 (1H, d, J=2.1Hz).

Elementary analysis C₄₀H₅₁N₅O₄S.0.5H₂O, Calcd. C, 67.96; H, 7.41; N,9.91. Found. C, 67.86; H, 7.23; N, 9.67.

[α]_(D)=−133.5° (C=0.260%, in ethanol)

EXAMPLE 51 Preparation of Compound 52

To a solution of(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-(3-methylpyrrolidin-1-yl)pyridin-3-yl]-2-methylacrylicacid (210 mg) in dichloromethane (10 ml) was added a drop of DMF, andthen oxalyl chloride (0.054 ml) at 0° C. The mixture was returned toroom temperature and stirred for 30 minutes under a nitrogen atmosphere.The solution was then added dropwise to a solution of4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfanyl]aniline (155 mg) inpyridine (10 ml) at 0° C. under a nitrogen atmosphere. The mixture wasreturned to room temperature and stirred for 3 hours. Then, water wasadded thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water twice and saturated brine once, andthen dried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was separated andpurified by basic silica gel column chromatography (hexane:ethylacetate=3:2→ethyl acetate) to give(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-(3-methylpyrrolidin-1-yl)pyridin-3-yl]-2-methyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfanyl]phenyl]acrylamide(270 mg) (Compound 52) as a yellow amorphous material.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.00 (3H, t, J=7.5Hz), 1.11 (3H, d, J=6.6 Hz), 1.36-1.45 (2H, m), 1.50-1.70 (3H, m),1.83-1.93 (2H, m), 2.05-2.15 (4H, m), 2.25-2.35 (1H, m), 3.10-3.20 (1H,m), 3.52-3.70 (5H, m), 3.81 (2H, t, J=4.5 Hz), 3.98 (2H, t, J=7.5 Hz),4.16 (2H, t, J=4.5 Hz), 4.21 (2H, s), 7.00 (2H, d, J=9.0 Hz), 7.33-7.65(9H, m), 8.08 (1H, s), 8.35 (1H, d, J=2.1 Hz).

Elementary analysis C₃₈H₄₈N₆O₃S.0.75H₂O, Calcd. C, 66.88; H, 7.31; N,12.32. Found. C, 66.79; H, 7.36; N, 12.04.

EXAMPLE 52 Preparation of Compound 53

To a solution of(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-(3-methylpyrrolidin-1-yl)pyridin-3-yl]-2-methyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfanyl]phenyl]acrylamide(200 mg) in dichloromethane (10 ml) was added dropwise at −78° C. asolution of 3-chloroperbenzoic acid (70%, 112 mg) in dichloromethane (10ml). After stirring the mixture as such for 30 minutes, the dryice-acetone bath was removed, and an aqueous sodium thiosulfate solutionwas added thereto while vigorously stirring. The resulting mixture wasreturned to room temperature and stirred for 30 minutes, which was thenextracted with ethyl acetate. The organic layer was washed with anaqueous saturated sodium hydrogen carbonate solution and saturatedbrine, and dried over magnesium sulfate. The solvent was distilled offunder reduced pressure, and then the resulting residue was separated andpurified by basic silica gel column chromatography (ethylacetate→methanol:ethyl acetate=1:19) to give(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-(3-methylpyrrolidin-1-yl)pyridin-3-yl]-2-methyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl]phenyl]acrylamide(112 mg) (Compound 53) as a yellow amorphous material.

¹H-NMR (200 MHz, CDCl₃) δ 0.90-0.99 (6H, m), 1.12 (3H, d, J=6.6 Hz),1.33-1.46 (2H, m), 1.50-1.85 (5H, m), 2.00-2.15 (4H, m), 2.20-2.40 (1H,m), 3.12-3.18 (1H, m), 3.45-3.66 (5H, m), 3.81 (2H, t, J=4.5 Hz), 4.00(2H, t, J=7.8 Hz), 4.10-4.23 (3H, m), 4.33 (1H, d, J=13.8 Hz), 7.00 (2H,d, J=8.7 Hz), 7.38-7.50 (5H, m), 7.61 (1H, s), 7.79-7.82 (3H, m), 8.13(1H, s), 8.35 (1H, d, J=2.4 Hz).

Elementary analysis C₃₈H₄₈N₆O₄S.0.5H₂O, Calcd. C, 65.77; H, 7.12; N,12.11. Found. C, 65.62; H, 7.29; N, 11.82.

EXAMPLE 53 Preparation of Compound 54

To a solution of(2E)-3-[2-[3-(acetoxymethyl)pyrrolidin-1-yl]-5-[4-(2-butoxyethoxy)phenyl]pyridin-3-yl]-2-methylacrylicacid (370 mg) in dichloromethane (10 ml) was added a drop of DMF, andthen oxalyl chloride (0.085 ml) at 0° C. The mixture was returned toroom temperature and stirred for 30 minutes under a nitrogen atmosphere.The solution was then added dropwise to a solution of4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfanyl]aniline (241 mg) inpyridine (10 ml) at 0° C. under a nitrogen atmosphere. The mixture wasreturned to room temperature and stirred for 3 hours. Then, water wasadded thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water twice and saturated brine once, andthen dried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was separated andpurified by basic silica gel column chromatography (hexane:ethylacetate=3:2→ethyl acetate) to give(2E)-3-[2-[3-(acetoxymethyl)pyrrolidin-1-yl]-5-[4-(2-butoxyethoxy)phenyl]pyridin-3-yl]-2-methyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfanyl]phenyl]acrylamide(388 mg) (Compound 54) as a yellow amorphous material.

¹H-NMR (200 MHz, CDCl₃) δ 0.91-1.03 (6H, m), 1.33-1.46 (2H, m),1.53-1.90 (5H, m), 2.03-2.10 (7H, m), 2.55-2.65 (1H, m), 3.36-3.41 (1H,m), 3.53-3.57 (4H, m), 3.63-3.69 (1H, m), 3.81 (2H, t, J=4.8 Hz), 3.98(2H, t, J=7.5 Hz), 4.05-4.17 (4H, m), 4.21 (2H, s), 7.00 (2H, d, J=9.0Hz), 7.35 (2H, d, J=9.0 Hz), 7.42 (2H, d, J=9.0 Hz), 7.51 (1H, d, J=2.4Hz), 7.55-7.59 (3H, m), 7.69 (1H, s), 8.07 (1H, s), 8.35 (1H, d, J=2.4Hz).

Elementary analysis C₄₀H₅₀N₆O₅S, Calcd. C, 66.09; H, 6.93; N, 11.56.Found. C, 65.92; H, 7.04; N, 11.59.

EXAMPLE 54 Preparation of Compound 55

To a solution of(2E)-3-[2-[3-(acetoxymethyl)pyrrolidin-1-yl]-5-[4-(2-butoxyethoxy)phenyl]pyridin-3-yl]-2-methyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfanyl]phenyl]acrylamide(Compound 54) (240 mg) in dichloromethane (10 ml) was added dropwise at−78° C. a solution of 3-chloroperbenzoic acid (70%, 106 mg) indichloromethane (10 ml). After stirring the mixture as such for 10minutes, the dry ice-acetone bath was removed, and an aqueous sodiumthiosulfate solution was added thereto while vigorously stirring. Theresulting mixture was returned to room temperature and stirred for 30minutes, which was extracted with ethyl acetate. The organic layer waswashed with an aqueous saturated sodium hydrogen carbonate solution andsaturated brine, and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue wasseparated and purified by basic silica gel column chromatography (ethylacetate→methanol:ethyl acetate=1:19) to give(2E)-3-[2-[3-(acetoxymethyl)pyrrolidin-1-yl]-5-[4-(2-butoxyethoxy)phenyl]pyridin-3-yl]-2-methyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl]phenyl]acrylamide(147 mg) (Compound 55) as a yellow amorphous material.

¹H-NMR (200 MHz, CDCl₃) δ 0.89-0.99 (6H, m), 1.36-1.43 (2H, m),1.55-1.83 (5H, m), 2.02-2.22 (7H, m), 2.55-2.65 (1H, m), 3.37-3.42 (1H,m), 3.50-3.57 (4H, m), 3.62-3.70 (1H, m), 3.80 (2H, t, J=4.8 Hz), 4.00(2H, t, J=7.8 Hz), 4.09-4.23 (5H, m), 4.32 (1H, d, J=14.1 Hz), 6.99 (2H,d, J=9.0 Hz), 7.40-7.57 (6H, m), 7.79-7.82 (3H, m), 8.12 (1H, s), 8.35(1H, d, J=2.1 Hz).

Elementary analysis C₄₀H₅₀N₆O₆S.0.5H₂O, Calcd. C, 63.89; H, 6.84; N,11.18. Found. C, 63.61; H, 6.75; N, 10.88.

EXAMPLE 55 Preparation of Compound 56

To a solution of(2E)-3-[2-[3-(acetoxymethyl)pyrrolidin-1-yl]-5-[4-(2-butoxyethoxy)phenyl]pyridin-3-yl]-2-methyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl]phenyl]acrylamide(Compound 55) (110 mg) in tetrahydrofuran (2 ml) and methanol (2 ml) wasadded a 1 N aqueous sodium hydroxide solution (0.222 ml), and themixture was stirred at room temperature for 5.5 hours. To the reactionsolution were added water and 1 N hydrochloric acid (0.25 ml), and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue wasseparated and purified by basic silica gel column chromatography (ethylacetate→methanol:ethyl acetate=1:6) to give(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-[3-(hydroxymethyl)pyrrolidin-1-yl]pyridin-3-yl]-2-methyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl]phenyl]acrylamide(74 mg) (Compound 56) as a yellow amorphous material.

¹H-NMR (200 MHz, CDCl₃) δ 0.90-0.98 (6H, m), 1.36-1.43 (2H, m),1.50-1.83 (5H, m), 2.00-2.55 (6H, m), 3.39-4.21 (15H, m), 4.31 (1H, d,J=12.6 Hz), 6.99 (2H, d, J=8.7 Hz), 7.32-7.60 (6H, m), 7.79-7.82 (2H,m), 8.11-8.14 (2H, m), 8.35 (1H, d, J=2.1 Hz).

Elementary analysis C₃₈H₄₈N₆O₅S.0.5H₂O, Calcd. C, 64.29; H, 6.96; N,11.84. Found. C, 64.19; H, 7.06; N, 11.61.

EXAMPLE 56 Preparation of Compounds 57 and 58

(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-[3-(methoxycarbonyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(300 mg) was resolved by using CHIRAKPAK AD (50 mmID×500 mL)(hexane:2-propanol=1:1) to give two diastereomers [the former fraction:diastereomer 1 (Compound 57) (147 mg, >99% de) and the latter fraction:diastereomer 2 (Compound 58) (146 mg, >99% de)].

Compound 57 [α]_(D)=−197.8° (C=0.177%, in ethanol)

Compound 58 [α]_(D)=−44.2° (C=0.175%, in ethanol)

EXAMPLE 57 Preparation of Compound 59

The optically resolved(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-[3-(methoxycarbonyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(75 mg) (the former fraction: diastereomer 1 (Compound 57)) in Example56 was dissolved in tetrahydrofuran (2.5 ml) and methanol (2.5 ml), anda 1 N aqueous sodium hydroxide solution (0.31 ml) was added thereto. Themixture was stirred for 7 hours under a nitrogen atmosphere and lightshielding. After adding 1 N hydrochloric acid (0.5 ml), water andsaturated brine were added thereto, and the mixture was extracted withethyl acetate. The organic layer was dried over magnesium sulfate, andthen the solvent was distilled off under reduced pressure. The resultingresidue was recrystallized from methanol-acetone to give(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-carboxypyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(diastereomer 1 (Compound 59)) (21.0 mg, 99.0% de) as colorlesscrystals.

[α]_(D)=−376.1° (C=0.224%, in chloroform)

EXAMPLE 58 Preparation of Compound 60

The optically resolved(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-[3-(methoxycarbonyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(115 mg) (the latter fraction: diastereomer 2 (Compound 58)) in Example56 was dissolved in tetrahydrofuran (4 ml) and methanol (4 ml), and a 1N aqueous sodium hydroxide solution (0.47 ml) was added thereto. Themixture was stirred for 7 hours under a nitrogen atmosphere and lightshielding. After adding 1 N hydrochloric acid (0.75 ml), water andsaturated brine were added thereto, and the mixture was extracted withethyl acetate. The organic layer was dried over magnesium sulfate, andthen the solvent was distilled off under reduced pressure. The resultingresidue was recrystallized from methanol-acetone to give(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-carboxypyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(diastereomer 2 (Compound 60)) (26.9 mg, 99.8% de) as colorlesscrystals.

[α]_(D)=+76.6° (C=0.208%, in chloroform)

EXAMPLE 59 Preparation of Compound 61

(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]anilinedi-p-toluoyl-D-tartrate monohydrate (1.20 g) was dissolved in ethylacetate (10 ml) and 1 N hydrochloric acid (6.09 ml), followed byseparation. To the aqueous layer was added an aqueous 25% potassiumcarbonate solution (6.09 ml), followed by extraction with2-propanol-ethyl acetate (1:4) twice. The organic layers were combined,washed with saturated brine and dried over magnesium sulfate, and thenthe solvent was distilled off under reduced pressure. To the resultingresidue was added toluene, and then the solvent was again distilled offunder reduced pressure to give(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline. To asolution of(2E)-3-[4′-(2-butoxyethoxy)-4-[3-(2-ethoxy-2-oxoethyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methylacrylicacid (700 mg) in tetrahydrofuran (10 ml) was added a drop of DMF, andthen oxalyl chloride (0.156 ml) at 0° C. The mixture was returned toroom temperature and stirred for 30 minutes under a nitrogen atmosphere.The solution was then added dropwise to a solution of(S)-4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]aniline and pyridine(2.89 ml) in tetrahydrofuran (10 ml) at 0° C. under a nitrogenatmosphere. The mixture was returned to room temperature and stirredovernight. Then, water was added thereto and the mixture was extractedwith ethyl acetate. The organic layer was washed with water twice andsaturated brine once, and then dried over magnesium sulfate. The solventwas distilled off under reduced pressure, and then the resulting residuewas separated and purified by basic silica gel column chromatography(ethyl acetate→methanol:ethyl acetate=3:100) to give(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-[3-(2-ethoxy-2-oxoethyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methyl-N-(4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(710 mg) (Compound 61) as a yellow amorphous material.

¹H-NMR (300 MHz, CDCl₃) δ 0.89-0.96 (6H, m), 1.25 (3H, t, J=7.2 Hz),1.30-1.43 (2H, m), 1.55-1.80 (5H, m), 2.10-2.25 (4H, m), 2.47-2.49 (2H,m), 2.60-2.75 (1H, m), 3.08-3.13 (2H, m), 3.25-3.45 (3H, m), 3.55 (2H,t, J=6.9 Hz), 3.77-3.82 (4H, m), 4.02-4.17 (6H, m), 6.59 (1H, s), 6.89(1H, d, J=8.1 Hz), 6.98 (2H, d, J=8.7 Hz), 7.34-7.47 (7H, m), 7.57 (1H,s), 7.80 (2H, d, J=8.7 Hz), 7.95 (1H, s).

Elementary analysis C₄₃H₅₄N₄O₆S.0.5H₂O, Calcd. C, 67.60; H, 7.26; N,7.33. Found. C, 67.41; H, 7.26; N, 7.25.

[α]_(D)=−108.3° (C=0.492%, in ethanol)

EXAMPLE 60 Preparation of Compound 62

To a solution of(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-[3-(2-ethoxy-2-oxoethyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(360 mg) in tetrahydrofuran (10 ml) and methanol (10 ml) was added a 1 Naqueous sodium hydroxide solution (1.43 ml), and the mixture was stirredfor 1 day at room temperature. To the reaction solution were addedwater, 1 N hydrochloric acid (2.0 ml) and saturated brine, and themixture was then extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over magnesium sulfate. Thesolvent was distilled off under reduced pressure, and then the resultingresidue was separated and purified by preparative HPLC to give(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-[3-(carboxymethyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide(182 mg) (Compound 62) as a yellow amorphous material.

Elementary analysis C₄₁H₅₀N₄O₆S.0.5H₂O, Calcd. C, 66.91; H, 6.98; N,7.61. Found. C, 66.71; H, 6.99; N, 7.47.

[α]_(D)=−118.5° (C=0.501%, in ethanol)

REFERENCE EXAMPLE 1

A mixture of 5-bromo-2-fluorobenzaldehyde (5.0 g, 24.6 mmol),hexahydro-1H-azepine (3.33 ml, 29.5 mmol) and potassium carbonate (5.1g, 36.9 mmol) in DMF (50 ml) was stirred at 80° C. for 20 hours. To thereaction system was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane=1:19) to give2-azepan-1-yl-5-bromobenzaldehyde (5.2 g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.51-1.86 (8H, m), 3.56-3.41 (4H, m), 6.96(1H, d, J=9.0 Hz), 7.46 (1H, dd, J=9.0, 2.6 Hz), 7.82 (1H, d, J=2.6 Hz),10.10 (1H, s).

IR (neat) 1680, 1588, 1481, 1404, 1267, 1175 cm⁻¹

REFERENCE EXAMPLE 2

To a solution of 2-azepan-1-yl-5-bromobenzaldehyde (1.0 g) and ethylacetate (0.42 ml) in dimethyl carbonate (10 ml) was added sodiummethoxide (28% solution in methanol, 2.2 g) at room temperature, and themixture was stirred at 50° C. for 20 hours. 1 N Hydrochloric acid wasadded to the reaction system until the pH reached 3 to 4, and theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane=1:19) to giveethyl (2E)-3-(2-azepan-1-yl-5-bromophenyl)acrylate (0.96 g) as a yellowoily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.34 (3H, t, J=7.1 Hz), 1.63-1.86 (8H, m),3.05-3.19 (4H, m), 4.26 (2H, q, J=7.1 Hz), 6.30 (1H, d, J=16.2 Hz), 6.95(1H, d, J=8.8 Hz), 7.35 (1H, dd, J=8.8, 2.6 Hz), 7.58 (1H, d, J=2.6 Hz),7.99 (1H, d, J=16.2 Hz).

IR (neat) 1713, 1630, 1480, 1260, 1177, 912, 743 cm⁻¹

REFERENCE EXAMPLE 3

Under an argon atmosphere, a mixture of ethyl(2E)-3-(2-azepan-1-yl-5-bromophenyl)acrylate (0.96 g),4-(2-butoxyethoxy)phenylboric acid (0.78 g) and potassium carbonate(0.75 g) in toluene (30 ml), ethanol (3 ml) and water (3 ml) was stirredfor 1 hour at room temperature. Tetrakis(triphenylphosphine)palladium(0.16 g) was added to the reaction system, and the mixture was heatedunder reflux for 6 hours. After cooling to room temperature, theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane=1:19→1:15) togive ethyl(2E)-3-[4-azepan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]acrylate(842 mg) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.3 Hz), 1.28-1.48 (5H, m),1.53-1.67 (2H, m), 1.69-1.90 (8H, m), 3.12-3.26 (4H, m), 3.55 (2H, t,J=6.6 Hz), 3.81 (2H, t, J=4.8 Hz), 4.16 (2H, t, J=4.8 Hz), 4.28 (2H, q,J=6.9 Hz), 6.40 (1H, d, J=16.1 Hz), 6.98 (2H, d, J=8.8 Hz), 7.13 (1H, d,J=8.8 Hz), 7.44-7.51 (3H, m), 7.67 (1H, d, J=2.2 Hz), 8.51 (1H, d,J=16.1 Hz).

IR (neat) 1709, 1630, 1607, 1487, 1453, 1302, 1246, 1175, 1125, 820 cm⁻¹

REFERENCE EXAMPLE 4

To a solution of ethyl(2E)-3-[4-azepan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]acrylate(842 mg, 1.81 mmol) in THF (5 ml) and ethanol (10 ml) was added a 1 Naqueous sodium hydroxide solution (4.0 ml, 4.0 mmol) at roomtemperature, and the mixture was stirred at 60° C. for 24 hours. Aftercooling to room temperature, 1 N hydrochloric acid (4.0 ml) was addedthereto, and the resulting mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over magnesiumsulfate. After concentration under reduced pressure, the precipitatedcrystals were collected by filtration. The crystals were washed withdiisopropyl ether and hexane to give(2E)-3-[4-azepan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]acrylicacid (551 mg) as yellow crystals.

m.p. 135-138° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.34-1.46 (2H, m),1.57-1.66 (2H, m), 1.70-1.86 (8H, m), 3.21-3.25 (4H, m), 3.56 (2H, t,J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 4.17 (2H, t, J=5.0 Hz), 6.41 (1H, d,J=15.9 Hz), 6.99 (2H, d, J=9.0 Hz), 7.15 (1H, d, J=8.7 Hz), 7.47-7.52(3H, m), 7.68 (1H, d, J=2.4 Hz), 8.24 (1H, d, J=15.9 Hz).

IR (KBr) 1692, 1618, 1605, 1487, 1327, 1304, 1279, 1246, 1117, 816 cm⁻¹

Elementary analysis C₂₇H₃₅NO₄, Calcd. C, 74.11; H, 8.06; N, 3.20. Found.C, 74.18; H, 8.07; N, 2.98.

REFERENCE EXAMPLE 5

To a solution of 2-azepan-1-yl-5-bromobenzaldehyde (2.0 g) and methylpropionate (0.75 ml) in dimethyl carbonate (20 ml) was added sodiummethoxide (28% solution in methanol, 2.0 g), and the mixture was stirredat 60° C. for 64 hours. After neutralization with 1 N hydrochloric acid,the resulting mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over magnesium sulfate.After concentration under reduced pressure, the residue was separatedand purified by column chromatography (ethyl acetate:hexane=1:99) togive methyl (2E)-3-(2-azepan-1-yl-5-bromophenyl)-2-methylacrylate (1.306g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 1.63-1.78 (8H, m), 2.06 (3H, d, J=1.5 Hz),3.12-3.15 (4H, m), 3.82 (3H, s), 6.91 (1H, d, J=9.3 Hz), 7.29-7.33 (2H,m), 7.69 (1H, s).

IR (neat) 1713, 1481, 1449, 1275, 1248, 1192, 1119, 909, 737 cm⁻¹

REFERENCE EXAMPLE 6

Under an argon atmosphere, a mixture of methyl(2E)-3-(2-azepan-1-yl-5-bromophenyl)-2-methylacrylate (1.3 g),4-(2-butoxyethoxy)phenylboric acid (1.05 g) and potassium carbonate(1.02 g) in toluene (40 ml), ethanol (4 ml) and water (4 ml) was stirredfor 1 hour at room temperature. Tetrakis(triphenylphosphine)palladium(0.20 g) was added to the reaction system, and the mixture was heatedunder reflux for 5 hours. After cooling to room temperature, water wasadded thereto, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover magnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by column chromatography (ethylacetate:hexane=1:19) to give methyl(2E)-3-[4-azepan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]-2-methylacrylate(1.38 g) as yellow crystals.

m.p. 86-89° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.5 Hz), 1.34-1.46 (2H, m),1.55-1.66 (2H, m), 1.67-1.82 (8H, m), 2.13 (3H, d, J=1.8 Hz), 3.18-3.22(4H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 3.83 (3H, s),4.15 (2H, t, J=5.0 Hz), 6.98 (2H, d, J=8.7 Hz), 7.09 (1H, d, J=9.3 Hz),7.41-7.48 (4H, m), 7.85 (1H, s).

IR (KBr) 1711, 1605, 1487, 1273, 1246, 1119, 909, 820, 737 cm⁻¹

Elementary analysis C₂₉H₃₉NO₄, Calcd. C, 74.81; H, 8.44; N, 3.01. Found.C, 74.83; H, 8.38; N, 2.88.

REFERENCE EXAMPLE 7

To a solution of methyl(2E)-3-[4-azepan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]-2-methylacrylate(1.38 g) in THF (5 ml) and ethanol (10 ml) was added a 1 N aqueoussodium hydroxide solution (5.0 ml) at room temperature, and the mixturewas stirred at 60° C. for 5 days. 1 N Hydrochloric acid (5.0 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over magnesium sulfate. After concentration under reducedpressure, the precipitated crystals were collected by filtration. Thecrystals were washed with diisopropyl ether to give(2E)-3-[4-azepan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]2-methylacrylicacid (877.9 mg) as yellow crystals.

m.p. 124-126° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.32-1.45 (2H, m),1.56-1.66 (2H, m), 1.67-1.84 (8H, m), 2.16 (3H, d, J=1.5 Hz), 3.20-3.23(4H, m), 3.55 (2H, t, J=6.8 Hz), 3.81 (2H, t, J=5.0 Hz), 4.10 (2H, t,J=5.0 Hz), 6.98 (2H, d, J=8.7 Hz), 7.11 (1H, d, J=9.0 Hz), 7.42-7.48(4H, m), 7.99 (1H, s).

IR (KBr) 1663, 1605, 1590, 1495, 1316, 1246, 1182, 1117, 1046, 831 cm⁻¹

Elementary analysis C₂₈H₃₇NO₄, Calcd. C, 74.47; H, 8.26; N, 3.10. Found.C, 74.30; H, 8.19; N, 2.93.

REFERENCE EXAMPLE 8

A mixture of 5-bromo-2-fluorobenzaldehyde (2.5 g), hexamethyleneimine(1.7 ml) and potassium carbonate (2.5 g) in DMF (25 ml) was stirred at80° C. for 16 hours. To the reaction system was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane=1:19) to give2-azocan-1-yl-5-bromobenzaldehyde (2.91 g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 1.55-1.80 (10H, m), 3.39-3.42 (4H, m), 7.00(1H, d, J=9.0 Hz), 7.47 (1H, dd, J=9.0, 2.6 Hz), 7.82 (1H, d, J=2.6 Hz),10.17 (1H, s).

REFERENCE EXAMPLE 9

To a solution of 2-azocan-1-yl-5-bromobenzaldehyde (2.9 g) and ethylacetate (1.24 ml) in diethyl carbonate (30 ml) was added sodium ethoxide(20% solution in ethanol, 5.0 g), and the mixture was stirred at 50° C.for 18 hours. After neutralization with 1 N hydrochloric acid, theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane=1:19) to giveethyl (2E)-3-(2-azocan-1-yl-5-bromophenyl)acrylate (2.77 g) as a yellowoily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.34 (3H, t, J=7.1 Hz), 1.61-1.80 (10H, m),3.06-3.21 (4H, m), 4.26 (2H, q, J=7.1 Hz), 6.28 (1H, d, J=15.9 Hz), 7.02(1H, d, J=8.6 Hz), 7.37 (1H, dd, J=8.6, 2.5 Hz), 7.59 (1H, d, J=2.5 Hz),8.11 (1H, d, J=15.9 Hz).

IR (neat) 1713, 1480, 1312, 1264, 1177, 909, 737 cm⁻¹

REFERENCE EXAMPLE 10

Under an argon atmosphere, a mixture of ethyl(2E)-3-(2-azocan-1-yl-5-bromophenyl)acrylate (2.77 g),4-(2-butoxyethoxy)phenylboric acid (2.16 g) and potassium carbonate(2.09 g) in toluene (80 ml), ethanol (8 ml) and water (8 ml) was stirredfor 1 hour at room temperature. Tetrakis(triphenylphosphine)palladium(0.44 g) was added to the reaction system, and the mixture was heatedunder reflux for 6 hours. After cooling to room temperature, water wasadded thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasseparated and purified by column chromatography (ethylacetate:hexane=1:19) to give ethyl(2E)-3-[4-azocan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]acrylate(2.97 g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.3 Hz), 1.25-1.48 (5H, m),1.53-1.84 (12H, m), 3.12-3.27 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.81 (2H,t, J=4.9 Hz), 4.16 (2H, t, J=4.9 Hz), 4.27 (2H, q, J=7.2 Hz), 6.38 (1H,d, J=16.3 Hz), 6.98 (2H, d, J=8.8 Hz), 7.21 (1H, d, J=8.8 Hz), 7.44-7.52(3H, m), 7.68 (1H, d, J=2.6 Hz), 8.27 (1H, d, J=16.3 Hz).

IR (neat) 1709, 1630, 1609, 1487, 1453, 1366, 1248, 1175, 1128, 1044,910, 826, 737 cm⁻¹

REFERENCE EXAMPLE 11

To a solution of ethyl(2E)-3-[4-azocan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]acrylate(2.97 g) in THF (30 ml) and ethanol (60 ml) was added a 1 N aqueoussodium hydroxide solution (12.0 ml) at room temperature, and the mixturewas stirred at 60° C. for 3 days. 1 N Hydrochloric acid (12.0 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over magnesium sulfate. After concentration under reducedpressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane=1:9→1:8→1:7→1:5) to give(2E)-3-[4-azocan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]acrylicacid (1.48 g) as yellow crystals.

¹H-NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J=7.2 Hz), 1.34-1.46 (2H, m),1.57-1.66 (2H, m), 1.67-1.85 (10H, m), 3.17-3.27 (4H, m), 3.56 (2H, t,J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 4.17 (2H, t, J=5.0 Hz), 6.39 (1H, d,J=16.0 Hz), 7.00 (2H, d, J=9.0 Hz), 7.21 (1H, d, J=8.7 Hz), 7.46-7.53(3H, m), 7.69 (1H, d, J=2.1 Hz), 8.35 (1H, d, J=16.0 Hz).

IR (KBr) 1682, 1620, 1607, 1487, 1451, 1418, 1271, 1246, 1208, 1127,1067, 831, 814 cm⁻¹

Elementary analysis C₂₈H₃₇NO₄, Calcd. C, 74.47; H, 8.26; N, 3.10. Found.C, 74.47; H, 8.28; N, 2.93.

REFERENCE EXAMPLE 12

A mixture of 5-bromo-2-fluorobenzaldehyde (2.5 g), diisobutylamine (2.8ml) and sodium carbonate (2.0 g) in DMSO (25 ml) and water (10 ml) washeated under reflux for 13 hours. After cooling to room temperature, theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with water and saturated brine, and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasseparated and purified by column chromatography (ethylacetate:hexane=1:49) to give 5-bromo-2-(diisobutylamino)benzaldehyde(1.93 g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.84 (12H, d, J=6.6 Hz), 1.82-1.98 (2H, m),3.10 (4H, d, J=7.5 Hz), 7.02 (1H, d, J=8.7 Hz), 7.50 (1H, dd, J=8.7, 2.7Hz), 7.85 (1H, d, J=2.7 Hz), 10.19 (1H, s).

IR (neat) 1684, 1586, 1480, 1468, 1389, 1254, 1177, 1152, 1113 cm⁻¹

REFERENCE EXAMPLE 13

To a suspension of sodium hydride (60%, 0.30 g) in toluene (30 ml) wasadded dropwise a solution of ethyl diethylphosphonoacetate (1.66 g) intoluene (10 ml) at 0° C. under a nitrogen atmosphere. After stirring at0° C. for 30 minutes, a solution of aldehyde (1.93 g) in toluene (20 ml)was added dropwise thereto, and the mixture was heated under reflux for2 hours. Then, water was added thereto, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over magnesium sulfate. After concentration under reducedpressure, the residue was separated and purified by column°chromatography (ethyl acetate:hexane=1:49) to give ethyl(2E)-3-[4′-(2-buthoxyethoxy)-4-(diisobutylamino)-1,1′-biphenyl-3-yl]acrylate(2.21 g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.86 (12H, d, J=6.6 Hz), 1.33 (3H, t, J=7.2Hz), 1.72-1.86 (2H, m), 2.75 (4H, d, J=7.2 Hz), 4.26 (2H, q, J=7.2 Hz),6.32 (1H, d, J=16.2 Hz), 7.01 (1H, d, J=8.7 Hz), 7.38 (1H, dd, J=8.7,2.4 Hz), 7.63 (1H, d, J=2.4 Hz), 8.08 (1H, d, J=16.2 Hz).

IR (neat) 1715, 1632, 1480, 1391, 1368, 1312, 1279, 1175, 909, 739 cm⁻¹

REFERENCE EXAMPLE 14

Under an argon atmosphere, a mixture of ethyl(2E)-3-[5-bromo-2-(diisobutylamino)phenyl]acrylate (2.21 g),4-(2-butoxyethoxy)phenylboric acid (1.65 g) and potassium carbonate(1.60 g) in toluene (60 ml), ethanol (6 ml) and water (6 ml) was stirredfor 1 hour at room temperature. Tetrakis(triphenylphosphine)palladium(0.33 g) was added to the reaction system, and the mixture was heatedunder reflux for 6 hours. After cooling to room temperature, water wasadded thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasseparated and purified by column chromatography (ethyl acetate:hexane1:49→1:29→1:19) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(diisobutylamino)-1,1′-biphenyl-3-yl]acrylate(2.12 g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.90 (12H, d, J=6.6 Hz), 0.94 (3H, t, J=7.5Hz), 1.32-1.45 (5H, m), 1.52-1.66 (2H, m), 1.78-1.92 (2H, m), 2.79 (4H,d, J=7.2 Hz), 3.56 (2H, t, J=6.8 Hz), 3.81 (2H, t, J=4.9 Hz), 4.17 (2H,t, J=4.9 Hz), 4.27 (2H, q, J=7.2 Hz), 6.41 (1H, d, J=16.2 Hz), 6.99 (2H,d, J=8.7 Hz), 7.19 (1H, d, J=8.7 Hz), 7.48-7.51 (3H, m), 7.71 (1H, d,J=2.4 Hz), 8.26 (1H, d, J=16.2 Hz).

IR (neat) 1711, 1630, 1487, 1466, 1277, 1248, 1177, 1127, 910, 737 cm⁻¹

REFERENCE EXAMPLE 15

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(diisobutylamino)-1,1′-biphenyl-3-yl]acrylate(2.12 g) in THF (10 ml) and ethanol (20 ml) was added a 1 N aqueoussodium hydroxide solution (10.0 ml) at room temperature, and the mixturewas stirred at 60° C. for 20 hours. 1 N Hydrochloric acid (10.0 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over magnesium sulfate. After concentration under reducedpressure, the precipitated crystals were collected by filtration. Thecrystals were washed with hexane to give(2E)-3-[4′-(2-butoxyethoxy)-4-(diisobutylamino)-1,1′-biphenyl-3-yl]acrylicacid (1.90 g) as yellow crystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.89 (12H, d, J=6.6 Hz), 0.93 (3H, t, J=7.4Hz), 1.30-1.48 (2H, m), 1.55-1.67 (2H, m), 1.75-1.96 (2H, m), 2.84 (4H,d, J=7.4 Hz), 3.56 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 4.17 (2H,t, J=5.0 Hz), 6.42 (1H, d, J=16.1 Hz), 6.99 (2H, d, J=8.8 Hz), 7.19 (1H,d, J=8.6 Hz), 7.47-7.54 (3H, m), 7.72 (1H, d, J=2.2 Hz), 8.32 (1H, d,J=16.1 Hz).

IR (KBr) 1707, 1674, 1624, 1485, 1275, 1244, 1128, 995, 814 cm⁻¹

Elementary analysis C₂₉H₄₁NO₄, Calcd. C, 74.48; H, 8.84; N, 3.00. Found.C, 74.36; H, 8.84; N, 2.92.

REFERENCE EXAMPLE 16

A mixture of 5-bromo-2-fluorobenzaldehyde (2.5 g), isobutylpropylaminehydrochloride (2.80 g) and sodium carbonate (3.91 g) in DMSO (25 ml) andwater (10 ml) was heated under reflux for 24 hours. After cooling toroom temperature, the resulting mixture was extracted with ethylacetate. The organic layer was washed with water and saturated brine,and dried over magnesium sulfate. After concentration under reducedpressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane=1:49) to give5-bromo-2-[isobutyl(propyl)amino]benzaldehyde (2.18 g) as a yellow oilymaterial.

To a suspension of sodium hydride (60%, 0.48 g) in toluene (10 ml) wasadded dropwise a solution of ethyl diethylphosphonoacetate (2.4 ml) intoluene (10 ml) at 0° C. under a nitrogen atmosphere. After stirring at0° C. for 30 minutes, a solution of5-bromo-2-[isobutyl(propyl)amino]benzaldehyde (2.18 g) in toluene (20ml) was added dropwise thereto, and the mixture was heated under refluxfor 2 hours. Then, water was added thereto, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over magnesium sulfate. After concentrationunder reduced pressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:49) to give ethyl(2E)-3-[5-bromo-2-[isobutyl(propyl)amino]phenyl]acrylate (1.96 g) as ayellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.81 (3H, t, J=7.5 Hz), 0.87 (6H, d, J=6.6Hz), 1.34 (3H, t, J=7.1 Hz), 1.41-1.54 (2H, m), 1.68-1.81 (1H, m), 2.79(2H, d, J=7.1 Hz), 2.85-2.90 (2H, m), 4.26 (2H, q, J=7.1 Hz), 6.33 (1H,d, J=16.2 Hz), 6.97 (1H, d, J=8.7 Hz), 7.38 (1H, dd, J=8.7, 2.4 Hz),7.64 (1H, d, J=2.4 Hz), 8.04 (1H, d, J=16.2 Hz).

IR (neat) 1717, 1480, 1312, 1275, 1179, 1111, 1034, 909, 739 cm⁻¹

REFERENCE EXAMPLE 17

Under an argon atmosphere, a mixture of ethyl(2E)-3-[5-bromo-2-[isobutyl(propyl)amino]phenyl]acrylate (1.96 g),4-(2-butoxyethoxy)phenylboric acid (1.51 g) and potassium carbonate(1.47 g) in toluene (50 ml), ethanol (5 ml) and water (5 ml) was stirredfor 1 hour at room temperature. Tetrakis(triphenylphosphine)palladium(0.30 g) was added to the reaction system, and the mixture was heatedunder reflux for 6 hours. After cooling to room temperature, water wasadded thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasseparated and purified by column chromatography (ethyl acetate:hexane1:29→1:19) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-[isobutyl(propyl)amino]-1,1′-biphenyl-3-yl]acrylate(1.56 g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.83 (3H, t, J=7.4 Hz), 0.91 (6H, d, J=6.6Hz), 0.93 (3H, t, J=7.4 Hz), 1.32-1.66 (9H, m) 1.74-1.85 (1H, m),2.81-2.96 (4H, m), 3.56 (2H, t, J=6.6 Hz) 3.81 (2H, t, J=5.0 Hz), 4.17(2H, t, J=5.0 Hz), 4.27 (2H, q, J=7.1 Hz), 6.43 (1H, d, J=16.4 Hz), 6.99(2H, d, J=8.7 Hz), 7.16 (1H, d, J=8.7 Hz), 7.47-7.50 (3H, m), 7.71 (1H,d, J=2.4 Hz), 8.20 (1H, d, J=16.4 Hz).

IR (neat) 1711, 1487, 1279, 1248, 1175, 909, 737 cm⁻¹

REFERENCE EXAMPLE 18

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-[isobutyl(propyl)amino]-1,1′-biphenyl-3-yl]acrylate(1.56 g) in THF (10 ml) and ethanol (20 ml) was added a 1 N aqueoussodium hydroxide solution (6.5 ml) at room temperature, and the mixturewas stirred at 60° C. for 20 hours. 1 N Hydrochloric acid (6.5 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over magnesium sulfate. After concentration under reducedpressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:9→1:3→1:2) to give(2E)-3-[4′-(2-butoxyethoxy)-4-[isobutyl(propyl)amino]-1,1′-biphenyl-3-yl]acrylicacid (1.03 g) as yellow crystals.

¹H-NMR (300 MHz, CDCl₃) δ 0.83 (3H, t, J=7.4 Hz), 0.91 (6H, d, J=6.6Hz), 0.94 (3H, t, J=7.4 Hz), 1.33-1.65 (6H, m), 1.74-1.87 (1H, m), 2.87(2H, d, J=7.5 Hz), 2.92-2.97 (2H, m), 3.56 (2H, t, J=6.8 Hz), 3.82 (2H,t, J=5.0 Hz), 4.17 (2H, t, J=5.0 Hz), 6.45 (1H, d, J=16.2 Hz), 7.00 (2H,d, J=9.0 Hz), 7.16 (1H, d, J=8.7 Hz), 7.48-7.53 (3H, m), 7.73 (1H, d,J=2.4 Hz), 8.29 (1H, d, J=16.2 Hz).

IR (KBr) 1707, 1688, 1626, 1485, 1279, 1248, 1127, 1071, 995, 818 cm⁻¹

Elementary analysis C₂₈H₃₉NO₄, Calcd. C, 74.14; H, 8.67; N, 3.09. Found.C, 73.90; H, 8.47; N, 3.08.

REFERENCE EXAMPLE 19

A mixture of 5-bromo-2-fluorobenzaldehyde (2.5 g), isobutylmethylamine(1.61 g) and sodium carbonate (2.60 g) in DMSO (40 ml) and water (25 ml)was heated under reflux for 20 hours. After cooling to room temperature,the resulting mixture was extracted with ethyl acetate. The organiclayer was washed with water and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by column chromatography (ethylacetate:hexane=1:29) to give5-bromo-2-[isobutyl(methyl)amino]benzaldehyde (3.14 g) as a yellow oilymaterial.

¹H-NMR (300 MHz, CDCl₃) δ 0.90 (6H, d, J=6.6 Hz), 1.89-2.04 (1H, m),2.89 (3H, s), 2.93 (2H, d, J=7.2 Hz), 6.98 (1H, d, J=8.7 Hz), 7.52 (1H,dd, J=8.7, 2.6 Hz), 7.86 (1H, d, J=2.6 Hz), 10.19 (1H, s).

IR (neat) 1684, 1588, 1485, 1389, 1260, 1179, 1154, 1113, 912, 880, 741cm⁻¹

REFERENCE EXAMPLE 20

To a suspension of sodium hydride (60%, 0.55 g) in toluene (50 ml) wasadded dropwise a solution of ethyl diethylphosphonoacetate (2.7 ml) intoluene (10 ml) at 0° C. under a nitrogen atmosphere. After stirring at0° C. for 30 minutes, a solution of5-bromo-2-[isobutyl(methyl)amino]benzaldehyde (3.14 g) in toluene (20ml) was added dropwise thereto, and the mixture was heated under refluxfor 2 hours. Then, water was added thereto, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over magnesium sulfate. After concentrationunder reduced pressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane=1:29) to give ethyl(2E)-3-[5-bromo-2-[isobutyl(methyl)amino]phenyl]acrylate (3.72 g) as ayellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.92 (6H, d, J=6.6 Hz), 1.34 (3H, t, J=7.1Hz), 1.81-1.96 (1H, m), 2.67 (3H, s), 2.69 (2H, d, J=7.2 Hz), 4.26 (2H,q, J=7.1 Hz), 6.35 (1H, d, J=16.2 Hz), 6.95 (1H, d, J=8.7 Hz), 7.39 (1H,dd, J=8.7, 2.4 Hz), 7.62 (1H, d, J=2.4 Hz), 8.00 (1H, d, J=16.2 Hz).

IR (neat) 1713, 1632, 1481, 1314, 1175, 912, 743 cm⁻¹

REFERENCE EXAMPLE 21

Under an argon atmosphere, a mixture of ethyl(2E)-3-[5-bromo-2-[isobutyl(methyl)amino]phenyl]acrylate (3.72 g),4-(2-butoxyethoxy)phenylboric acid (3.11 g) and potassium carbonate(3.01 g) in toluene (100 ml), ethanol (10 ml) and water (10 ml) wasstirred for 1 hour at room temperature.Tetrakis(triphenylphosphine)palladium (0.63 g) was added to the reactionsystem, and the mixture was heated under reflux for 6 hours. Aftercooling to room temperature, water was added thereto and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over magnesium sulfate. After concentrationunder reduced pressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:29→1:19) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-[isobutyl(methyl)amino]-1,1′-biphenyl-3-yl]acrylate(3.29 g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.4 Hz), 0.95 (6H, d, J=6.6Hz), 1.32-1.44 (5H, m), 1.54-1.66 (2H, m), 1.85-2.01 (1H, m), 2.72 (3H,s), 2.74 (2H, d, J=7.2 Hz), 3.55 (2H, t, J=6.8 Hz), 3.80 (2H, t, J=5.0Hz), 4.16 (2H, t, J=5.0 Hz), 4.27 (2H, q, J=7.1 Hz) 6.44 (1H, d, J=16.4Hz), 6.98 (2H, d, J=9.0 Hz), 7.12 (1H, d, J=8.4 Hz), 7.44-7.51 (3H, m),7.68 (1H, d, J=2.1 Hz), 8.15 (1H, d, J=16.4 Hz).

IR (neat) 1711, 1489, 1300, 1246, 1177, 1127, 912, 823 cm⁻¹

REFERENCE EXAMPLE 22

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-[isobutyl(methyl)amino]-1,1′-biphenyl-3-yl]acrylate(3.49 g) in THF (10 ml) and ethanol (20 ml) was added a 1 N aqueoussodium hydroxide solution (15 ml) at room temperature, and the mixturewas stirred at 60° C. for 2 days. 1 N Hydrochloric acid (15 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over magnesium sulfate. After concentration under reducedpressure, the precipitated crystals were collected by filtration. Thecrystals were washed with ethyl acetate and hexane to give(2E)-3-[4′-(2-butoxyethoxy)-4-[isobutyl(methyl)amino]-1,1′-biphenyl-3-yl]acrylicacid (2.61 g) as yellow crystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.90-0.97 (9H, m), 1.28-1.47 (2H, m),1.52-1.71 (2H, m), 1.82-2.05 (1H, m), 2.74 (3H, s), 2.78 (2H, d, J=7.4Hz), 3.56 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 4.17 (2H, t, J=5.0Hz), 6.47 (1H, d, J=16.1 Hz), 7.00 (2H, d, J=8.8 Hz) 7.14 (1H, d, J=8.6Hz), 7.46-7.55 (3H, m), 7.71 (1H, d, J=2.2 Hz), 8.26 (1H, d, J=16.1 Hz).

IR (KBr) 1686, 1624, 1487, 1466, 1422, 1300, 1269, 1246, 1182, 1127,1065, 974, 924, 826 cm⁻¹

Elementary analysis C₂₆H₃₅NO₄, Calcd. C, 73.38; H, 8.29; N, 3.29. Found.C, 73.15; H, 8.35; N, 3.32.

REFERENCE EXAMPLE 23

To a suspension of sodium hydride (60%, 0.39 g) in toluene (10 ml) wasadded dropwise a solution of ethyl 2-(diethylphosphono)butyrate (2.47 g)in toluene (10 ml) at 0° C. under a nitrogen atmosphere. After stirringat room temperature for 1 hour, a solution of2-azepan-1-yl-5-bromobenzaldehyde (2.3 g) in toluene (20 ml) was addeddropwise thereto. The reaction mixture was heated under reflux for 5hours. Then, water was added thereto, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over magnesium sulfate. After concentration under reducedpressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane=1:39) to give ethyl(2E)-3-(2-azepan-1-yl-5-bromophenyl)-2-ethylacrylate (2.95 g) as ayellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.14 (3H, t, J=7.5 Hz), 1.34 (3H, t, J=7.2Hz), 1.62-1.82 (8H, m), 2.52 (2H, q, J=7.5 Hz), 3.04-3.18 (4H, m), 4.28(2H, q, J=7.2 Hz), 6.90 (1H, d, J=9.2 Hz), 7.26-7.33 (2H, m), 7.65 (1H,s).

IR (neat) 1709, 1480, 1235, 1130, 912, 743 cm⁻¹

REFERENCE EXAMPLE 24

Under an argon atmosphere, a mixture of ethyl(2E)-3-(2-azepan-1-yl-5-bromophenyl)-2-ethylacrylate (2.95 g),4-(2-butoxyethoxy)phenylboric acid (2.21 g) and potassium carbonate(2.14 g) in toluene (80 ml), ethanol (8 ml) and water (8 ml) was stirredfor 1 hour at room temperature. Tetrakis(triphenylphosphine)palladium(0.45 g) was added to the reaction system, and the mixture was heatedunder reflux for 7 hours. After cooling to room temperature, water wasadded thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasseparated and purified by column chromatography (ethyl acetate:hexane1:39→1:19→1:9) to give ethyl(2E)-3-[4-azepan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]-2-ethylacrylate(2.63 g) as pale yellow crystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.1 Hz), 1.19 (3H, t, J=7.3Hz), 1.30-1.46 (5H, m), 1.51-1.84 (10H, m), 2.61 (2H, q, J=7.3 Hz),3.16-3.22 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16(2H, t, J=5.0 Hz), 4.29 (2H, q, J=7.1 Hz), 6.98 (2H, d, J=8.8 Hz), 7.09(1H, d, J=9.2 Hz), 7.40-7.48 (4H, m), 7.81 (1H, s).

IR (KBr) 1707, 1607, 1489, 1454, 1246, 1128, 818 cm⁻¹

Elementary analysis C₃₁H₄₃NO₄, Calcd. C, 75.42; H, 8.78; N, 2.84. Found.C, 75.39; H, 8.61; N, 2.61.

REFERENCE EXAMPLE 25

To a solution of ethyl(2E)-3-[4-azepan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]-2-ethylacrylate(2.63 g) in THF (20 ml) and ethanol (40 ml) was added a 1 N aqueoussodium hydroxide solution (12 ml) at room temperature, and the mixturewas stirred at 60° C. for 20 hours. 1 N Hydrochloric acid (12 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over magnesium sulfate. After concentration under reducedpressure, the precipitated crystals were collected by filtration to give(2E)-3-[4-azepan-1-yl-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]-2-ethylacrylicacid (1.90 g) as yellow crystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.1 Hz), 1.24 (3H, t, J=7.4Hz), 1.31-1.48 (2H, m), 1.52-1.86 (10H, m), 2.63 (2H, q, J=7.4 Hz),3.19-3.24 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16(2H, t, J=5.0 Hz), 6.99 (2H, d, J=8.8 Hz), 7.10 (1H, d, J=9.2 Hz),7.44-7.48 (4H, m), 7.96 (1H, s).

IR (KBr) 1672, 1603, 1487, 1472, 1453, 1296, 1244, 1123, 816 cm⁻¹

Elementary analysis C₂₉H₃₉NO₄, Calcd. C, 74.08; H, 8.47; N, 2.98. Found.C, 73.98; H, 8.53; N, 2.73.

REFERENCE EXAMPLE 26

A mixture of 5-bromo-2-fluorobenzaldehyde (2.5 g), ethylisobutylaminehydrochloride (2.7 g) and sodium carbonate (4.16 g) in DMSO (25 ml) andwater (10 ml) was heated under reflux for 5 hours. After cooling to roomtemperature, the resulting mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by column chromatography (ethylacetate:hexane 1:49) to give5-bromo-2-[ethyl(isobutyl)amino]benzaldehyde (1.90 g) as a yellow oilymaterial. To a suspension of sodium hydride (60%, 0.35 g) in toluene (20ml) was added dropwise a solution of ethyl diethylphosphonoacetate (1.6ml) in toluene (5 ml) at 0° C. under a nitrogen atmosphere. Afterstirring at 0° C. for 30 minutes, a solution of5-bromo-2-[ethyl(isobutyl)amino]benzaldehyde (1.90 g) in toluene (10 ml)was added dropwise thereto, and the mixture was heated under reflux for2 hours. Then, water was added thereto, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over magnesium sulfate. After concentration under reducedpressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:49) to give ethyl(2E)-3-[5-bromo-2-[ethyl(isobutyl)amino]phenyl]acrylate (1.38 g) as ayellow oily material. A mixture of ethyl(2E)-3-[5-bromo-2-[ethyl(isobutyl)amino]phenyl]acrylate (1.38 g),4-(2-butoxyethoxy)phenylboric acid (1.21 g) and potassium carbonate(1.08 g) in toluene (40 ml), ethanol (4 ml) and water (4 ml) was stirredfor 1 hour at room temperature under an argon atmosphere.Tetrakis(triphenylphosphine)palladium (0.23 g) was added to the reactionsystem, and the mixture was heated under reflux for 4 hours. Aftercooling to room temperature, water was added thereto and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over magnesium sulfate. After concentrationunder reduced pressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:29→1:19) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-[ethyl(isobutyl)amino]-1,1′-biphenyl-3-yl]acrylate(947 mg) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.90-1.07 (12H, m), 1.30-1.50 (5H, m),1.52-1.67 (2H, m), 1.71-1.88 (1H, m), 2.85 (2H, d, J=7.2 Hz), 3.02 (2H,q, J=7.1 Hz), 3.56 (2H, t, J=6.4 Hz), 3.81 (2H, t, J=4.9 Hz), 4.17 (2H,t, J=4.9 Hz), 4.27 (2H, q, J=7.2 Hz), 6.44 (1H, d, J=16.0 Hz), 6.99 (2H,d, J=8.8 Hz), 7.14 (1H, d, J=8.8 Hz), 7.47-7.52 (3H, m), 7.72 (1H, d,J=2.2 Hz), 8.18 (1H, d, J=16.0 Hz).

IR (neat) 1711, 1488, 1277, 1248, 1175, 912, 743 cm⁻¹

REFERENCE EXAMPLE 27

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-[ethyl(isobutyl)amino]-1,1′-biphenyl-3-yl]acrylate(947 mg) in THF (5 ml) and ethanol (10 ml) was added a 1 N aqueoussodium hydroxide solution (4.0 ml) at room temperature, and the mixturewas stirred at 60° C. for 20 hours. 1 N Hydrochloric acid (4.0 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over magnesium sulfate. After concentration under reducedpressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:2) to give(2E)-3-[4′-(2-butoxyethoxy)-4-[ethyl(isobutyl)amino]-1,1′-biphenyl-3-yl]acrylicacid (870.3 mg) as yellow crystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.90-1.08 (12H, m), 1.30-1.47 (2H, m),1.52-1.88 (3H, m), 2.87 (2H, d, J=7.4 Hz), 3.04 (2H, q, J=7.1 Hz), 3.56(2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz) 4.17 (2H, t, J=5.0 Hz), 6.45(1H, d, J=16.6 Hz), 7.00 (2H, d, J=8.8 Hz), 7.16 (1H, d, J=8.4 Hz),7.47-7.55 (3H, m), 7.73 (1H, d, J=2.2 Hz), 8.28 (1H, d, J=16.6 Hz).

IR (KBr) 1684, 1628, 1603, 1485, 1279, 1248, 1127, 1071, 820 cm⁻¹

Elementary analysis C₂₇H₃₇NO₄, Calcd. C, 73.77; H, 7.48; N, 3.19. Found.C, 73.51; H, 8.42; N, 2.91.

REFERENCE EXAMPLE 28

A mixture of 5-bromo-2-fluorobenzaldehyde (2.5 g), piperidine (1.46 ml)and potassium carbonate (2.70 g) in DMF (25 ml) was stirred at 80° C.for 3 days. Water was added to the reaction system, and the resultingmixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane=1:49) to give5-bromo-2-piperidin-1-ylbenzaldehyde (2.20 g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.50-1.82 (6H, m), 3.00-3.05 (4H, m), 6.98(1H, d, J=8.6 Hz), 7.57 (1H, dd, J=8.6, 2.6 Hz), 7.89 (1H, d, J=2.6 Hz),10.20 (1H, s).

IR (neat) 1682, 1586, 1480, 1466, 1379, 1258, 1227, 1177, 912, 820, 747cm⁻¹

REFERENCE EXAMPLE 29

To a suspension of sodium hydride (60%, 0.18 g) in toluene (10 ml) wasadded dropwise a solution of ethyl diethylphosphonoacetate (1.01 g) intoluene (5 ml) at 0° C. under a nitrogen atmosphere. After stirring at0° C. for 30 minutes, a solution of 2-piperidin-5-bromobenzaldehyde (1.0g) in toluene (20 ml) was added dropwise thereto. The reaction mixturewas heated under reflux for 3 hours. Then, water was added thereto, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane=1:49) to giveethyl (2E)-3-(5-bromo-2-piperidin-1-ylphenyl)acrylate (1.22 g) as ayellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.31 (3H, t, J=7.2 Hz), 1.50-1.82 (6H, m),2.84-2.89 (4H, m), 4.27 (2H, q, J=7.2 Hz), 6.37 (1H, d, J=16.1 Hz), 6.89(1H, d, J=8.6 Hz), 7.40 (1H, dd, J=8.6, 2.2 Hz), 7.62 (1H, d, J=2.2 Hz),7.95 (1H, d, J=16.1 Hz).

IR (neat) 1717, 1634, 1480, 1312, 1262, 1233, 1181, 1125, 1105, 1028,912, 814, 743 cm⁻¹

REFERENCE EXAMPLE 30

Under an argon atmosphere, a mixture of ethyl(2E)-3-(5-bromo-2-piperidin-1-ylphenyl)acrylate (1.22 g),4-(2-butoxyethoxy)phenylboric acid (1.03 g) and potassium carbonate(1.00 g) in toluene (36 ml), ethanol (3.6 ml) and water (3.6 ml) wasstirred for 1 hour at room temperature.Tetrakis(triphenylphosphine)palladium (0.20 g) was added to the reactionsystem, and the mixture was heated under reflux for 7 hours. Aftercooling to room temperature, water was added thereto, and the resultingmixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:19→1:9) togive ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-piperidin-1-yl-1,1′-biphenyl-3-yl]acrylate(1.53 g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.1 Hz), 1.30-1.46 (5H, m),1.51-1.67 (4H, m), 1.70-1.85 (4H, m), 2.91-2.96 (4H, m), 3.55 (2H, t,J=6.4 Hz), 3.80 (2H, t, J=4.8 Hz), 4.16 (2H, t, J=4.8 Hz), 4.26 (2H, q,J=7.2 Hz), 6.47 (1H, d, J=16.3 Hz), 6.98 (2H, d, J=8.6 Hz), 7.07 (1H, d,J=8.4 Hz), 7.44-7.54 (3H, m), 7.70 (1H, d, J=2.2 Hz), 8.10 (1H, d,J=16.3 Hz)

IR (neat) 1713, 1634, 1607, 1487, 1248, 1231, 1177, 1125, 1038, 820 cm⁻¹

REFERENCE EXAMPLE 31

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-piperidin-1-yl-1,1′-biphenyl-3-yl]acrylate(1.53 g) in THF (5 ml) and ethanol (10 ml) was added a 1 N aqueoussodium hydroxide solution (7.0 ml) at room temperature, and the mixturewas stirred at 65° C. for 3 days. 1 N Hydrochloric acid (7.0 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over magnesium sulfate. After concentration under reducedpressure, the precipitated crystals were collected by filtration. Thecrystals were washed with diisopropyl ether to give(2E)-3-[4′-(2-butoxyethoxy)-4-piperidin-1-yl-1,1′-biphenyl-3-yl]acrylicacid (1.13 g) as yellow crystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.3 Hz), 1.30-1.45 (2H, m),1.52-1.69 (4H, m), 1.72-1.87 (4H, m), 2.92-2.97 (4H, m), 3.56 (2H, t,J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 4.17 (2H, t, J=5.0 Hz), 6.49 (1H, d,J=16.2 Hz), 6.99 (2H, d, J=8.8 Hz), 7.09 (1H, d, J=8.4 Hz), 7.44-7.56(3H, m), 7.72 (1H, d, J=2.2 Hz), 8.21 (1H, d, J=16.2 Hz).

IR (KBr) 1684, 1624, 1607, 1489, 1302, 1248, 1231, 1121, 820, 808 cm⁻¹

Elementary analysis C₂₆H₃₃NO₄, Calcd. C, 73.73; H, 7.85; N, 3.31. Found.C, 73.55; H, 7.81; N, 3.16.

REFERENCE EXAMPLE 32

To a suspension of sodium hydride (60%, 0.21 g) in toluene (10 ml) wasadded dropwise a solution of ethyl 2-(diethylphosphono)propionate. (1.28g) in toluene (5 ml) at 0° C. under a nitrogen atmosphere. Afterstirring at 0° C. for 1 hour, a solution of5-bromo-2-piperidin-1-ylbenzaldehyde (1.2 g) in toluene (20 ml) wasadded dropwise thereto. The reaction mixture was heated under reflux for3 hours. Then, water was added thereto, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over magnesium sulfate. After concentration under reducedpressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane=1:49) to give ethyl(2E)-3-(5-bromo-2-piperidin-1-ylphenyl)-2-methylacrylate (1.47 g) as ayellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.35 (3H, t, J=7.1 Hz), 1.46-1.80 (6H, m),2.09-2.10 (3H, m), 2.82-2.87 (4H, m), 4.28 (2H, q, J=7.1 Hz), 6.85 (1H,d, J=8.4 Hz), 7.34-7.41 (2H, m), 7.72 (1H, s).

IR (neat) 1709, 1480, 1451, 1275, 1250, 1233, 1130, 1113, 814 cm⁻¹

REFERENCE EXAMPLE 33

Under an argon atmosphere, a mixture of ethyl(2E)-3-(5-bromo-2-piperidin-1-ylphenyl)-2-methylacrylate (1.47 g),4-(2-butoxyethoxy)phenylboric acid (1.19 g) and potassium carbonate(1.15 g) in toluene (40 ml), ethanol (4 ml) and water (4 ml) was stirredfor 1 hour at room temperature. Tetrakis(triphenylphosphine)palladium(0.24 g) was added to the reaction system, and the mixture was heatedunder reflux for 6 hours. After cooling to room temperature, water wasadded thereto, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with saturated brine, and driedover magnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by column chromatography (ethylacetate:hexane 1:29→1:19) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-piperidin-1-yl-1,1′-biphenyl-3-yl]-2-methylacrylate(1.68 g) as pale yellow crystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.28-1.45 (5H, m),1.49-1.79 (8H, m), 2.17 (3H, d, J=1.6 Hz), 2.89-2.94 (4H, m), 3.55 (2H,t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 4.29 (2H,q, J=7.2 Hz), 6.96-7.05 (3H, m), 7.44-7.48 (4H, m), 7.87 (1H, s).

IR (neat) 1703, 1605, 1485, 1271, 1240, 1128, 1111, 820 cm⁻¹

REFERENCE EXAMPLE 34

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-piperidin-1-yl-1,1′-biphenyl-3-yl]-2-methylacrylate(1.58 g) in THF (5 ml) and ethanol (10 ml) was added a 1 N aqueoussodium hydroxide solution (7.0 ml) at room temperature, and the mixturewas stirred at 65° C. for 20 hours. 1 N Hydrochloric acid (7.0 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over magnesium sulfate. After concentration under reducedpressure, the precipitated crystals were collected by filtration. Thecrystals were washed with diisopropyl ether and hexane to give(2E)-3-[4′-(2-butoxyethoxy)-4-piperidin-1-yl-1,1′-biphenyl-3-yl]-2-methylacrylicacid (1.11 mg) as yellow crystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.1 Hz), 1.28-1.84 (10H, m),2.19 (3H, d, J=1.4 Hz), 2.86-2.96 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.80(2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 6.99 (2H, d, J=8.8 Hz), 7.06(1H, d, J=8.0 Hz), 7.44-7.51 (4H, m), 8.00 (1H, s).

IR (KBr) 1678, 1609, 1487, 1450, 1285, 1235, 1132, 826 cm⁻¹

Elementary analysis C₂₇H₃₅NO₄, Calcd. C, 74.11; H, 8.06; N, 3.20. Found.C, 73.39; H, 7.98; N, 3.07.

REFERENCE EXAMPLE 35

A mixture of 5-bromo-2-fluorobenzaldehyde (2.5 g), pyrrolidine (1.33 ml)and potassium carbonate (2.55 g) in DMF (25 ml) was stirred at 80° C.for 4 days. Water was added to the reaction system, and the resultingmixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:19→1:9) togive 5-bromo-2-pyrrolidin-1-ylbenzaldehyde (2.50 g) as a yellow oilymaterial.

¹H-NMR (300 MHz, CDCl₃) δ 1.98-2.02 (4H, m), 3.32-3.37 (4H, m), 6.71(1H, d, J=9.0 Hz), 7.41 (1H, dd, J=9.0, 2.7 Hz), 7.78 (1H, d, J=2.7 Hz),10.01 (1H, s).

IR (neat) 1667, 1593, 1480, 1462, 1406, 1167, 912, 743 cm⁻¹

REFERENCE EXAMPLE 36

To a suspension of sodium hydride (60%, 0.236 g) in toluene (10 ml) wasadded dropwise a solution of ethyl diethylphosphonoacetate (1.32 g) intoluene (10 ml) at 0° C. under a nitrogen atmosphere. After stirring at0° C. for 1 hour, a solution of 5-bromo-2-pyrrolidin-1-ylbenzaldehyde(1.25 g) in toluene (10 ml) was added dropwise thereto. The reactionmixture was heated under reflux for 4 hours. Then, water was addedthereto, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over magnesium sulfate.After concentration under reduced pressure, the residue was separatedand purified by column chromatography (ethyl acetate:hexane 1:15→1:9) togive ethyl (2E)-3-(5-bromo-2-pyrrolidin-1-ylphenyl)acrylate (1.387 g) asa yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.33 (3H, t, J=7.1 Hz), 1.90-1.97 (4H, m),3.23-3.29 (4H, m), 4.25 (2H, q, J=7.1 Hz), 6.21 (1H, d, J=15.8 Hz), 6.71(1H, d, J=9.0 Hz), 7.29 (1H, dd, J=9.0, 2.4 Hz), 7.49 (1H, d, J=2.4 Hz),7.93 (1H, d, J=15.8 Hz).

IR (neat) 1711, 1628, 1480, 1314, 1175, 912, 743 cm⁻¹

REFERENCE EXAMPLE 37

Under an argon atmosphere, a mixture of ethyl(2E)-3-(5-bromo-2-pyrrolidin-1-ylphenyl)acrylate (1.387 g),4-(2-butoxyethoxy)phenylboric acid (1.22 g) and potassium carbonate(1.18 g) in toluene (40 ml), ethanol (4.0 ml) and water (4.0 ml) wasstirred for 1 hour at room temperature.Tetrakis(triphenylphosphine)palladium (0.24 g) was added to the reactionsystem, and the mixture was heated under reflux for 6 hours. Aftercooling to room temperature, water was added thereto, and the resultingmixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:19→1:9) togive ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]acrylate(0.835 g) as yellow crystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.1 Hz), 1.30-1.45 (5H, m),1.51-1.69 (2H, m), 1.92-1.99 (4H, m), 3.29-3.36 (4H, m), 3.55 (2H, t,J=6.6 Hz), 3.80 (2H, t, J=4.9 Hz), 4.16 (2H, t, J=4.9 Hz), 4.26 (2H, q,J=7.1 Hz), 6.31 (1H, d, J=16.0 Hz), 6.91 (1H, d, J=8.8 Hz), 6.97 (2H, d,J=8.6 Hz), 7.41-7.48 (3H, m), 7.60 (1H, d, J=2.2 Hz), 8.08 (1H, d,J=16.0 Hz).

REFERENCE EXAMPLE 38

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]acrylate(0.835 g) in THF (5 ml) and ethanol (10 ml) was added a 1 N aqueoussodium hydroxide solution (4.0 ml) at room temperature, and the mixturewas stirred at 60° C. for 2 days. 1 N Hydrochloric acid (4.0 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over magnesium sulfate. After concentration under reducedpressure, the precipitated crystals were collected by filtration. Thecrystals were washed with diisopropyl ether to give(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]acrylicacid (707 mg) as yellow crystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.29-1.48 (2H, m),1.51-1.66 (2H, m), 1.94-2.00 (4H, m), 3.31-3.38 (4H, m), 3.55 (2H, t,J=6.6 Hz), 3.81 (2H, t, J=4.9 Hz), 4.16 (2H, t, J=4.9 Hz), 6.32 (1H, d,J=15.8 Hz), 6.92 (1H, d, J=8.8 Hz), 6.98 (2H, d, J=8.6 Hz), 7.44-7.49(3H, m), 7.62 (1H, d, J=2.2 Hz), 8.19 (1H, d, J=15.8 Hz).

Elementary analysis C₂₅H₃₁NO₄, Calcd. C, 73.32; H, 7.63; N, 3.42. Found.C, 73.11; H, 7.54; N, 3.24.

REFERENCE EXAMPLE 39

To a suspension of sodium hydride (60%, 0.235 g) in toluene (10 ml) wasadded dropwise a solution of ethyl 2-(diethylphosphono)propionate (1.40g) in toluene (10 ml) at 0° C. under a nitrogen atmosphere. Afterstirring at 0° C. for 1 hour, a solution of aldehyde (1.25 g) in toluene(10 ml) was added dropwise thereto. The reaction mixture was heatedunder reflux for 6 hours. Then, water was added thereto, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane=1:19) to giveethyl (2E)-3-(5-bromo-2-pyrrolidin-1-ylphenyl)-2-methylacrylate (1.489g) as a pale yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.34 (3H, t, J=7.1 Hz), 1.87-1.94 (4H, m),1.97 (3H, d, J=1.6 Hz), 3.15-3.21 (4H, m), 4.26 (2H, q, J=7.1 Hz), 6.66(1H, d, J=8.4 Hz), 7.19-7.29 (2H, m), 7.67 (1H, s).

IR (neat) 1709, 1478, 1273, 1111, 912, 745 cm⁻¹

REFERENCE EXAMPLE 40

Under an argon atmosphere, a mixture of ethyl(2E)-3-(5-bromo-2-pyrrolidin-1-ylphenyl)-2-methylacrylate (1.489 g),4-(2-butoxyethoxy)phenylboric acid (1.26 g) and potassium carbonate(1.22 g) in toluene (45 ml), ethanol (4.5 ml) and water (4.5 ml) wasstirred for 1 hour at room temperature.Tetrakis(triphenylphosphine)palladium (0.25 g) was added to the reactionsystem, and the mixture was heated under reflux for 6 hours. Aftercooling to room temperature, water was added thereto, and the resultingmixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:19→1:9) togive ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]-2-methylacrylate(1.51 g) as pale yellow crystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.3 Hz), 1.29-1.48 (5H, m),1.51-1.68 (2H, m), 1.89-1.95 (4H, m), 2.04 (3H, d, J=1.4 Hz), 3.22-3.28(4H, m), 3.55 (2H, t, J=6.8 Hz), 3.80 (2H, t, J=4.9 Hz), 4.15 (2H, t,J=4.9 Hz), 4.27 (2H, q, J=7.1 Hz), 6.86 (1H, d, J=8.4 Hz), 6.96 (2H, d,J=8.8 Hz), 7.32-7.48 (4H, m), 7.83 (1H, s).

IR (KBr) 1705, 1605, 1495, 1483, 1271, 1246, 1113, 909, 737 cm⁻¹

Elementary analysis C₂₈H₃₇NO₄, Calcd. C, 74.47; H, 8.26; N, 3.10. Found.C, 74.34; H, 8.32; N, 2.89.

REFERENCE EXAMPLE 41

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]-2-methylacrylate(1.46 g) in THF (5 ml) and ethanol (10 ml) was added a 1 N aqueoussodium hydroxide solution (7.0 ml) at room temperature, and the mixturewas stirred at 60° C. for 3 days. 1 N Hydrochloric acid (7.0 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over magnesium sulfate. After concentration under reducedpressure, the precipitated crystals were collected by filtration. Thecrystals were washed with diisopropyl ether and hexane to give(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]-2-methylacrylicacid (1.04 g) as yellow crystals.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.34-1.71 (4H, m),1.91-1.95 (4H, m), 2.07 (3H, d, J=1.2 Hz), 3.24-3.29 (4H, m), 3.54 (2H,t, J=6.6 Hz), 3.80 (2H, t, J=5.0 Hz), 4.15 (2H, t, J=5.0 Hz), 6.87 (1H,d, J=8.7 Hz), 6.96 (2H, d, J=9.0 Hz), 7.34-7.46 (4H, m), 7.95 (1H, s).

IR (KBr) 1671, 1607, 1483, 1287, 1244, 1123, 816 cm⁻¹

Elementary analysis C₂₆H₃₃NO₄, Calcd. C, 73.73; H, 7.85; N, 3.31. Found.C, 73.53; H, 7.71; N, 3.10.

REFERENCE EXAMPLE 42

A mixture of 5-bromo-2-fluorobenzaldehyde (2.50 g), 4-methylpiperidine(1.46 ml) and potassium carbonate (2.55 g) in DMF (25 ml) was stirred at80° C. for 3 days. Water was added to the reaction system, and theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with water and saturated brine, and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasseparated and purified by column chromatography (ethyl acetate:hexane1:49) to give 5-bromo-(4-methylpiperidin-1-yl)benzaldehyde (2.95 g) as ayellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.06 (3H, d, J=5.8 Hz), 1.31-1.55 (3H, m),1.71-1.83 (2H, m), 2.81-2.92 (2H, m), 3.16-3.29 (2H, m), 6.98 (1H, d,J=8.8 Hz), 7.56 (1H, dd, J=8.8, 2.6 Hz), 7.88 (1H, d, J=2.6 Hz), 10.19(1H, s).

IR (neat) 1682, 1586, 1480, 1464, 1379, 1219, 910, 737 cm⁻¹

REFERENCE EXAMPLE 43

To a suspension of sodium hydride (60%, 0.24 g) in toluene (10 ml) wasadded dropwise a solution of ethyl diethylphosphonoacetate (1.18 ml) intoluene (10 ml) at 0° C. under an argon atmosphere. After stirring at 0°C. for 1 hour, a solution of5-bromo-(4-methylpiperidin-1-yl)benzaldehyde (1.40 g) in toluene (10 ml)was added thereto, and the resulting mixture was heated under reflux for4 hours. Water was added to the reaction system and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:49) to giveethyl (2E)-3-[5-bromo-2-(4-methylpiperidin-1-yl)phenyl]acrylate (1.59 g)as yellow crystals.

¹H-NMR (200 MHz, CDCl₃) δ 1.00 (3H, d, J=5.6 Hz), 1.31-1.56 (6H, m),1.63-1.79 (2H, m), 2.56-2.72 (2H, m), 3.03-3.16 (2H, m), 4.27 (2H, q,J=7.1 Hz), 6.37 (1H, d, J=16.1 Hz), 6.89 (1H, d, J=8.4 Hz), 7.39 (1H,dd, J=8.4, 2.6 Hz), 7.62 (1H, d, J=2.6 Hz), 7.94 (1H, d, J=16.1 Hz).

Elementary analysis C₁₇H₂₂NO₂Br, Calcd. C, 57.96; H, 6.29; N, 3.98.Found. C, 57.80; H, 6.12; N, 3.86.

REFERENCE EXAMPLE 44

Under an argon atmosphere, a mixture of ethyl(2E)-3-[5-bromo-2-(4-methylpiperidin-1-yl)phenyl]acrylate (1.47 g),4-(2-butoxyethoxy)phenylboric acid (1.24 g) and potassium carbonate(1.11 g) in toluene (40 ml), ethanol (4 ml) and water (4 ml) was stirredfor 1 hour at room temperature. Tetrakis(triphenylphosphine)palladium(0.23 g) was added to the reaction system, and the mixture was heatedunder reflux for 6 hours. After cooling to room temperature, water wasadded thereto, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water and saturated brine,and dried over magnesium sulfate. After concentration under reducedpressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:39→1:19→1:9) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(4-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]acrylate(1.83 g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.02 (3H, d, J=5.2Hz), 1.28-1.82 12H, m), 2.64-2.79 (2H, m), 3.11-3.24 (2H, m), 3.56 (2H,t, J=6.6 Hz), 3.81 (2H, t, J=4.9 Hz), 4.17 (2H, t, J=4.9 Hz), 4.28 (2H,q, J=7.1 Hz), 6.47 (1H, d, J=16.2 Hz), 6.99 (2H, d, J=8.8 Hz), 7.08 (1H,d, J=8.4 Hz), 7.44-7.54 (3H, m), 7.70 (1H, d, J=2.2 Hz), 8.09 (1H, d,J=16.2 Hz).

IR (neat) 1711, 1487, 1246, 1223, 1177, 822 cm⁻¹

REFERENCE EXAMPLE 45

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(4-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]acrylate(1.83 g) in ethanol (10 ml) and THF (5 ml) was added a 1 N aqueoussodium hydroxide solution (8.0 ml) at room temperature, and the mixturewas stirred at 60° C. for 20 hours. 1 N Hydrochloric acid (8.0 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the precipitated crystals were collected byfiltration. The crystals were washed with diisopropyl ether and hexaneto give(2E)-3-[4′-(2-butoxyethoxy)-4-(4-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]acrylicacid (1.556 g) as yellow crystals.

m.p. 159-160° C.

¹H-NMR (200 MHz, CDCl₃) δ 0.94 (3H, t, J=7.2 Hz), 1.03 (3H, d, J=4.8Hz), 1.31-1.82 (9H, m), 2.64-2.80 (2H, m), 3.11-3.25 (2H, m), 3.56 (2H,t, J=6.6 Hz), 3.82 (2H, t, J=5.0 Hz), 4.17 (2H, t, J=5.0 Hz), 6.49 (1H,d, J=16.3 Hz), 7.00 (2H, d, J=8.8 Hz), 7.10 (1H, d, J=8.4 Hz), 7.47-7.57(3H, m), 7.72 (1H, d, J=2.2 Hz), 8.19 (1H, d, J=16.3 Hz).

Elementary analysis C₂₇H₃₅NO₄, Calcd. C, 74.11; H, 8.06; N, 3.20. Found.C, 73.92; H, 7.96; N, 2.98.

REFERENCE EXAMPLE 46

To a suspension of sodium hydride (60%, 0.26 g) in toluene (10 ml) wasadded dropwise a solution of ethyl 2-(diethylphosphono)propionate (1.57ml) in toluene (5.0 ml) at 0° C. under an argon atmosphere. Afterstirring at 0° C. for 1 hour, a solution of5-bromo-(4-methylpiperidin-1-yl)benzaldehyde (1.55 g) in toluene (20 ml)was added thereto, and the mixture was heated under reflux for 5 hours.Water was added to the reaction system, and the resulting mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:49) to giveethyl (2E)-3-[5-bromo-2-(4-methylpiperidin-1-yl)phenyl]-2-methylacrylate(2.0 g) as yellow crystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.98 (3H, d, J=5.8 Hz), 1.23-1.49 (6H, m),1.61-1.76 (2H, m), 2.10 (3H, d, J=1.0 Hz), 2.53-2.68 (2H, m), 3.04-3.16(2H, m), 4.28 (2H, q, J=7.2 Hz), 6.86 (1H, d, J=8.4 Hz), 7.34-7.41 (2H,m), 7.71 (1H, s).

IR (neat) 1709, 1464, 1277, 1254, 1225, 1132, 1115, 909, 737 cm⁻¹

REFERENCE EXAMPLE 47

Under an argon atmosphere, a mixture of ethyl(2E)-3-[5-bromo-2-(4-methylpiperidin-1-yl)phenyl]-2-methylacrylate (2.00g), 4-(2-butoxyethoxy)phenylboric acid (1.69 g) and potassium carbonate(1.51 g) in toluene (50 ml), ethanol (5 ml) and water (5 ml) was stirredfor 1 hour at room temperature. Tetrakis(triphenylphosphine)palladium(0.19 g) was added to the reaction system, and the mixture was heatedunder reflux for 6 hours. After cooling to room temperature, theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with water and saturated brine, and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasseparated and purified by column chromatography (ethyl acetate:hexane1:39→1:19→1:9) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(4-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylate(2.30 g) as yellow crystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.3 Hz), 1.00 (3H, d, J=5.4Hz), 1.28-1.79 (12H, m), 2.17 (3H, d, J=1.6 Hz), 2.59-2.74 (2H, m),3.11-3.25 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=4.9 Hz), 4.16(2H, t, J=4.9 Hz), 4.30 (2H, q, J=7.1 Hz), 6.98 (2H, d, J=8.6 Hz), 7.04(1H, d, J=8.0 Hz), 7.44-7.48 (4H, m), 7.86 (1H, s).

IR (neat) 1705, 1607, 1487, 1273, 1244, 1130, 1117, 824 cm⁻¹

REFERENCE EXAMPLE 48

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(4-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylate(2.30 g) in ethanol (20 ml) and THF (10 ml) was added a 1 N aqueoussodium hydroxide solution (10.0 ml) at room temperature, and the mixturewas stirred at 60° C. for 4 days. 1 N Hydrochloric acid (10.0 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the precipitated crystals were collected byfiltration. The crystals were washed with diisopropyl ether and hexaneto give(2E)-3-[4′-(2-butoxyethoxy)-4-(4-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylicacid (1.60 g) as yellow crystals.

m.p. 154-155° C.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.3 Hz), 1.01 (3H, d, J=5.6Hz), 1.28-1.80 (9H, m), 2.20 (3H, d, J=1.4 Hz), 2.61-2.75 (2H, m),3.11-3.25 (2H, m), 3.56 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 4.17(2H, t, J=5.0 Hz), 6.99 (2H, d, J=8.8 Hz), 7.07 (1H, d, J=8.0 Hz),7.45-7.52 (4H, m), 8.00 (1H, s).

Elementary analysis C₂₈H₃₇NO₄, Calcd. C, 74.47; H, 8.26; N, 3.10. Found.C, 74.59; H, 8.39; N, 3.02.

REFERENCE EXAMPLE 49

To a suspension of sodium hydride (60%, 0.238 g) in toluene (10 ml) wasadded dropwise a solution of ethyl 2-(diethylphosphono)butyrate (1.41ml) in toluene (10 ml) at 0° C. under an argon atmosphere. Afterstirring at 0° C. for 1 hour, a solution of5-bromo-2-pyrrolidin-1-ylbenzaldehyde (1.263 g) in toluene (30 ml) wasadded thereto, and the mixture was heated under reflux for 6 hours.Water was added to the reaction system, and the resulting mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:9) to giveethyl (2E)-3-(5-bromo-2-pyrrolidin-1-ylphenyl)-2-ethylacrylate (1.666 g)as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.10 (3H, t, J=7.3 Hz), 1.34 (3H, t, J=7.1Hz), 1.87-1.94 (4H, m), 2.48 (2H, q, J=7.3 Hz), 3.17-3.23 (4H, m), 4.27(2H, q, J=7.1 Hz), 6.65 (1H, d, J=8.8 Hz), 7.20-7.29 (2H, m), 7.62 (1H,s).

IR (neat) 1709, 1480, 1236, 1128, 912, 741 cm⁻¹

REFERENCE EXAMPLE 50

Under an argon atmosphere, a mixture of ethyl(2E)-3-(5-bromo-2-pyrrolidin-1-ylphenyl)-2-ethylacrylate (1.666 g),4-(2-butoxyethoxy)phenylboric acid (1.35 g) and potassium carbonate(1.31 g) in toluene (50 ml), ethanol (5 ml) and water (5 ml) was stirredfor 1 hour at room temperature. Tetrakis(triphenylphosphine)palladium(0.16 g) was added to the reaction system, and the mixture was heatedunder reflux for 6 hours. After cooling to room temperature, theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with water and saturated brine, and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasseparated and purified by column chromatography (ethyl acetate:hexane1:19) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]-2-ethylacrylate(1.46 g) as pale yellow crystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.1 Hz), 1.15 (3H, t, J=7.3Hz), 1.29-1.48 (5H, m), 1.54-1.68 (2H, m), 1.89-1.95 (4H, m), 2.57 (2H,q, J=7.3 Hz), 3.24-3.31 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t,J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 4.28 (2H, q, J=7.1 Hz), 6.85 (1H, d,J=8.4 Hz), 6.97 (2H, d, J=8.6 Hz), 7.34-7.49 (4H, m), 7.77 (1H, s).

IR (neat) 1709, 1480, 1236, 1128, 912, 741 cm⁻¹

Elementary analysis C₂₉H₃₉NO₄, Calcd. C, 74.81; H, 8.44; N, 3.01. Found.C, 74.70; H, 8.53; N, 2.73.

REFERENCE EXAMPLE 51

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]-2-ethylacrylate(1.40 g) in ethanol (20 ml) and THF (10 ml) was added a 1 N aqueoussodium hydroxide solution (6.0 ml) at room temperature, and the mixturewas stirred at 65° C. for 24 hours. 1 N Hydrochloric acid (6.0 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the precipitated crystals were collected byfiltration. The crystals were washed with diisopropyl ether and hexaneto give(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]-2-ethylacrylicacid (962 mg) as yellow crystals.

m.p. 155-156° C.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.1 Hz), 1.21 (3H, t, J=7.5Hz), 1.30-1.48 (2H, m), 1.54-1.68 (2H, m), 1.90-1.99 (4H, m), 2.60 (2H,q, J=7.5 Hz), 3.26-3.33 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t,J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 6.87 (1H, d, J=8.8 Hz), 6.98 (2H, d,J=8.8 Hz), 7.37-7.48 (4H, m), 7.93 (1H, s).

Elementary analysis C₂₇H₃₅NO₄, Calcd. C, 74.11; H, 8.06; N, 3.20. Found.C, 73.98; H, 8.15; N, 3.22.

REFERENCE EXAMPLE 52

A mixture of 5-bromo-2-fluorobenzaldehyde (2.50 g), 2-methylpyrrolidine(1.63 ml) and sodium carbonate (2.6 g) in DMSO (25 ml) and water (5 ml)was stirred at 100° C. for 12 hours. Water was added to the reactionsystem, and the resulting mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasseparated and purified by column chromatography (ethyl acetate:hexane1:19→1:9) to give 5-bromo-2-(2-methylpyrrolidin-1-yl)benzaldehyde (2.76g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.20 (3H, d, J=5.8 Hz), 1.63-1.82 (2H, m),1.88-2.03 (1H, m), 2.08-2.32 (1H, m), 3.03-3.13 (1H, m), 3.69-3.96 (2H,m), 6.81 (1H, d, J=9.2 Hz), 7.44 (1H, dd, J=9.0, 2.6 Hz), 7.82 (1H, d,J=2.6 Hz), 10.04 (1H, s).

IR (neat) 1674, 1590, 1474, 1402, 1175, 912, 741 cm⁻¹

REFERENCE EXAMPLE 53

To a suspension of sodium hydride (60%, 0.25 g) in toluene (10 ml) wasadded dropwise a solution of ethyl diethylphosphonoacetate (1.23 ml) intoluene (10 ml) at 0° C. under an argon atmosphere. After stirring at 0°C. for 30 minutes, a solution of5-bromo-2-(2-methylpyrrolidin-1-yl)benzaldehyde (1.38 g) in toluene (20ml) was added thereto, and the resulting mixture was heated under refluxfor 3 hours. Water was added to the reaction system, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:19) to giveethyl (2E)-3-[5-bromo-2-(2-methylpyrrolidin-1-yl)phenyl]acrylate (1.64g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.06 (3H, d, J=6.0 Hz), 1.34 (3H, t, J=7.1Hz), 1.50-1.96 (3H, m), 2.06-2.24 (1H, m), 2.88-3.00 (1H, m), 3.52-3.76(2H, m), 4.26 (2H, q, J=7.1 Hz), 6.27 (1H, d, J=16.1 Hz), 6.80 (1H, d,J=8.6 Hz), 7.33 (1H, dd, J=8.6, 2.3 Hz), 7.55 (1H, d, J=2.3 Hz), 7.88(1H, d, J=16.1 Hz).

IR (neat) 1713, 1632, 1476, 1314, 1175, 1038, 909, 742 cm⁻¹

REFERENCE EXAMPLE 54

Under an argon atmosphere, a mixture of ethyl(2E)-3-[5-bromo-2-(2-methylpyrrolidin-1-yl)phenyl]acrylate (1.64 g),4-(2-butoxyethoxy)phenylboric acid (1.39 g) and potassium carbonate(1.24 g) in toluene (50 ml), ethanol (5 ml) and water (5 ml) was stirredfor 1 hour at room temperature. Tetrakis(triphenylphosphine)palladium(0.17 g) was added to the reaction system, and the mixture was heatedunder reflux for 6 hours. After cooling to room temperature, theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with water and saturated brine, and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasseparated and purified by column chromatography (ethyl acetate:hexane1:19→1:14→1:9) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(2-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]acrylate(1.87 g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.11 (3H, d, J=6.2Hz), 1.31-1.48 (6H, m), 1.61-1.98 (4H, m), 2.08-2.28 (1H, m), 2.91-3.06(1H, m), 3.56 (2H, t, J=6.6 Hz), 3.62-3.84 (4H, m), 4.16 (2H, t, J=4.8Hz), 4.27 (2H, q, J=7.1 Hz), 6.37 (1H, d, J=15.8 Hz), 6.98 (2H, d, J=8.8Hz), 6.99 (1H, d, J=8.4 Hz), 7.44-7.50 (3H, m), 7.64 (1H, d, J=2.0 Hz),8.04 (1H, d, J=15.8 Hz).

IR (neat) 1709, 1628, 1605, 1489, 1300, 1279, 1246, 1177, 1123, 910, 741cm⁻¹

REFERENCE EXAMPLE 55

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(2-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]acrylate(1.87 g) in ethanol (20 ml) and THF (10 ml) was added a 1 N aqueoussodium hydroxide solution (12.0 ml) at room temperature, and the mixturewas stirred at 65° C. for 20 hours. 1 N Hydrochloric acid (12.0 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the precipitated crystals were collected byfiltration. The crystals were washed with diisopropyl ether to give(2E)-3-[4′-(2-butoxyethoxy)-4-(2-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]acrylicacid (1.438 g) as yellow crystals.

m.p. 102-103° C.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.3 Hz), 1.13 (3H, d, J=5.8Hz), 1.29-1.49 (2H, m), 1.53-2.04 (5H, m), 2.08-2.29 (1H, m), 2.96-3.11(1H, m), 3.56 (2H, t, J=6.6 Hz), 3.60-3.84 (4H, m), 4.17 (2H, t, J=5.0Hz), 6.38 (1H, d, J=16.2 Hz), 6.97-7.02 (3H, m), 7.44-7.51 (3H, m), 7.66(1H, d, J=2.2 Hz), 8.15 (1H, d, J=16.2 Hz).

Elementary analysis C₂₆H₃₃NO₄, Calcd. C, 73.73; H, 7.85; N, 3.31. Found.C, 73.72; H, 7.69; N, 3.10.

REFERENCE EXAMPLE 56

To a suspension of sodium hydride (60%, 0.25 g) in toluene (10 ml) wasadded dropwise a solution of ethyl 2-(diethylphosphono)propionate (1.48g) in toluene (10 ml) at 0° C. under an argon atmosphere. After stirringat 0° C. for 1 hour, a solution of5-bromo-2-(2-methylpyrrolidin-1-yl)benzaldehyde (1.39 g) in toluene (20ml) was added thereto, and the resulting mixture was heated under refluxfor 7 hours. Water was added to the reaction system, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:19) to giveethyl(2E)-3-[5-bromo-2-(2-methylpyrrolidin-1-yl)phenyl]-2-methylacrylate(1.74 g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.04 (3H, d, J=5.8 Hz), 1.34 (3H, t, J=7.1Hz), 1.49-1.92 (3H, m), 2.00 (3H, d, J=1.6 Hz), 2.07-2.26 (1H, m),2.80-2.95 (1H, m), 3.38-3.49 (1H, m), 3.63-3.82 (1H, m), 4.27 (2H, q,J=7.1 Hz), 6.73 (1H, d, J=9.6 Hz), 7.21-7.31 (2H, m), 7.59 (1H, s).

IR (neat) 1709, 1476, 1273, 1250, 1111 cm⁻¹

REFERENCE EXAMPLE 57

Under an argon atmosphere, a mixture of ethyl(2E)-3-[5-bromo-2-(2-methylpyrrolidin-1-yl)phenyl]-2-methylacrylate(1.74 g), 4-(2-butoxyethoxy)phenylboric acid (1.41 g) and potassiumcarbonate (1.36 g) in toluene (50 ml), ethanol (5 ml) and water (5 ml)was stirred for 1 hour at room temperature.Tetrakis(triphenylphosphine)palladium (0.17 g) was added to the reactionsystem, and the mixture was heated under reflux for 6 hours. Aftercooling to room temperature, the resulting mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:19→1:9) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(2-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylate(1.528 g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.3 Hz), 1.11 (3H, d, J=6.2Hz), 1.28-1.48 (5H, m), 1.51-1.94 (5H, m), 2.07 (3H, d, J=1.4 Hz),2.08-2.25 (1H, m), 2.85-3.01 (1H, m), 3.45-3.58 (3H, m), 3.78-3.90 (3H,m), 4.16 (2H, t, J=4.8 Hz), 4.28 (2H, q, J=7.1 Hz), 6.90-6.99 (3H, m),7.38-7.48 (4H, m), 7.76 (1H, s).

IR (neat) 1705, 1489, 1269, 1244, 1115, 912, 743 cm⁻¹

REFERENCE EXAMPLE 58

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(2-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylate(1.528 g) in ethanol (20 ml) and THF (10 ml) was added a 1 N aqueoussodium hydroxide solution (10.0 ml) at room temperature, and the mixturewas stirred at 65° C. for 2 days. 1 N Hydrochloric acid (10.0 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the precipitated crystals were collected byfiltration. The crystals were washed with diisopropyl ether and hexaneto give(2E)-3-[4′-(2-butoxyethoxy)-4-(2-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylicacid (1.07 g) as yellow crystals.

m.p. 137-139° C.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.3 Hz), 1.12 (3H, d, J=6.0Hz), 1.28-1.49 (2H, m), 1.52-1.96 (5H, m), 2.05-2.27 (4H, m), 2.89-3.02(1H, m), 3.47-3.63 (3H, m), 3.75-3.89 (3H, m), 4.16 (2H, t, J=4.9 Hz),6.92-7.00 (3H, m), 7.41-7.48 (4H, m), 7.91 (1H, s).

Elementary analysis C₂₇H₃₅NO₄, Calcd. C, 74.11; H, 8.06; N, 3.20. Found.C, 74.08; H, 7.90; N, 3.10.

REFERENCE EXAMPLE 59

A mixture of 5-bromo-2-fluorobenzaldehyde (1.30 g), morpholine (0.67 g)and potassium carbonate (1.33 g) in DMF (10 ml) was stirred at 80° C.for 3 days. Water was added to the reaction system, and the resultingmixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:19→1:9→1:4) togive 5-bromo-2-morpholin-4-ylbenzaldehyde (720.5 mg) as pale yellowcrystals.

¹H-NMR (200 MHz, CDCl₃) δ 3.04-3.09 (4H, m), 3.87-3.92 (4H, m), 7.02(1H, d, J=8.4 Hz), 7.64 (1H, dd, J=8.4, 2.6 Hz), 7.92 (1H, d, J=2.6 Hz),10.26 (1H, s).

REFERENCE EXAMPLE 60

To a suspension of sodium hydride (60%, 0.266 g) in toluene (10 ml) wasadded dropwise a solution of ethyl diethylphosphonoacetate (1.32 ml) intoluene (10 ml) at 0° C. under an argon atmosphere. After stirring at 0°C. for 30 minutes, a solution of 5-bromo-2-morpholin-4-ylbenzaldehyde(1.5 g) in toluene (40 ml) was added thereto, and the resulting mixturewas heated under reflux for 3 hours. Water was added to the reactionsystem, and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by column chromatography (ethylacetate:hexane 1:9→1:4) to give ethyl(2E)-3-(5-bromo-2-morpholin-4-ylphenyl)acrylate (1.757 g) as pale yellowcrystals.

¹H-NMR (200 MHz, CDCl₃) δ 1.34 (3H, t, J=7.1 Hz), 2.90-2.95 (4H, m),3.86-3.90 (4H, m), 4.27 (2H, q, J=7.1 Hz), 6.39 (1H, d, J=16.1 Hz), 6.92(1H, d, J=8.8 Hz), 7.45 (1H, dd, J=8.8, 2.6 Hz), 7.65 (1H, d, J=2.6 Hz),7.97 (1H, d, J=16.1 Hz).

Elementary analysis C₁₅H₁₈NO₃Br, Calcd. C, 52.96; H, 5.33; N, 4.12.Found. C, 52.97; H, 5.32; N, 4.25.

REFERENCE EXAMPLE 61

Under an argon atmosphere, a mixture of ethyl(2E)-3-(5-bromo-2-morpholin-4-ylphenyl)acrylate (1.697 g),4-(2-butoxyethoxy)phenylboric acid (1.43 g) and potassium carbonate(1.38 g) in toluene (50 ml), ethanol (5 ml) and water (5 ml) was stirredfor 30 minutes at room temperature.Tetrakis(triphenylphosphine)palladium (0.17 g) was added to the reactionsystem, and the mixture was heated under reflux for 6 hours. Aftercooling to room temperature, the resulting mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:15→1:9→1:4) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-morpholin-4-yl-1,1′-biphenyl-3-yl]acrylate(2.176 g) as yellow crystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.29-1.49 (5H, m),1.55-1.69 (2H, m), 2.97-3.02 (4H, m), 3.56 (2H, t, J=6.8 Hz), 3.81 (2H,t, J=5.0 Hz), 3.89-3.94 (4H, m), 4.17 (2H, t, J=5.0 Hz), 4.28 (2H, q,J=7.1 Hz), 6.49 (1H, d, J=16.2 Hz), 7.00 (2H, d, J=8.8 Hz), 7.11 (1H, d,J=8.4 Hz), 7.49 (2H, d, J=8.8 Hz), 7.55 (1H, dd, J=8.4, 2.2 Hz), 7.72(1H, d, J=2.2 Hz), 8.12 (1H, d, J=16.2 Hz).

Elementary analysis C₂₇H₃₅NO₅, Calcd. C, 71.50; H, 7.78; N, 3.09. Found.C, 71.54; H, 7.95; N, 2.96.

REFERENCE EXAMPLE 62

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-morpholin-4-yl-1,1′-biphenyl-3-yl]acrylate(2.07 g) in ethanol (20 ml) and THF (10 ml) was added a 1 N aqueoussodium hydroxide solution (10.0 ml) at room temperature, and the mixturewas stirred at 65° C. for 4 hours. 1 N Hydrochloric acid (10.0 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the precipitated crystals were collected byfiltration. The crystals were washed with diisopropyl ether and hexaneto give(2E)-3-[4′-(2-butoxyethoxy)-4-morpholin-4-yl-1,1′-biphenyl-3-yl]acrylicacid (1.79 g) as yellow crystals.

m.p. 155-157° C.

¹H-NMR (200 MHz, CDCl₃) δ 0.94 (3H, t, J=7.3 Hz), 1.27-1.48 (2H, m),1.55-1.69 (2H, m), 2.98-3.03 (4H, m), 3.56 (2H, t, J=6.6 Hz), 3.82 (2H,t, J=5.0 Hz), 3.91-3.95 (4H, m), 4.18 (2H, t, J=5.0 Hz), 6.51 (1H, d,J=16.2 Hz), 7.01 (2H, d, J=8.4 Hz), 7.13 (1H, d, J=8.4 Hz), 7.50 (2H, d,J=8.4 Hz), 7.58 (1H, dd, J=8.4, 2.2 Hz), 7.74 (1H, d, J=2.2 Hz), 8.23(1H, d, J=16.2 Hz).

Elementary analysis C₂₅H₃₁NO₅, Calcd. C, 70.57; H, 7.34; N, 3.29. Found.C, 70.37; H, 7.53; N, 3.11.

REFERENCE EXAMPLE 63

A mixture of 5-bromo-2-fluorobenzaldehyde (1.35 g), methylpropylamine(0.54 g) and sodium carbonate (0.98 g) in DMSO (10 ml) and water (2.5ml) was stirred at 125° C. for 20 hours. The resulting mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:49→1:19) togive 5-bromo-2-[methyl(propyl)amino]benzaldehyde (1.43 g) as a yellowoily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.88 (3H, t, J=7.5 Hz), 1.52-1.71 (2H, m),2.87 (3H, s), 3.04-3.11 (2H, m), 6.97 (1H, d, J=8.8 Hz), 7.53 (1H, dd,J=8.8, 2.6 Hz), 7.87 (1H, d, J=2.6 Hz), 10.17 (1H, s).

REFERENCE EXAMPLE 64

To a suspension of sodium hydride (60%, 0.27 g) in toluene (10 ml) wasadded dropwise a solution of ethyl diethylphosphonoacetate (1.33 ml) intoluene (10 ml) at 0° C. under an argon atmosphere. After stirring at 0°C. for 30 minutes, a solution of5-bromo-2-[methyl(propyl)amino]benzaldehyde (1.43 g) in toluene (20 ml)was added thereto, and the resulting mixture was heated under reflux for2 hours. Water was added to the reaction system, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:19) to giveethyl (2E)-[5-bromo-2-[methyl(propyl)amino]phenyl]acrylate (1.86 g) as ayellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.89 (3H, t, J=7.4 Hz), 1.34 (3H, t, J=7.2Hz), 1.48-1.66 (2H, m), 2.71 (3H, s), 2.85 (2H, t, J=7.3 Hz), 4.27 (2H,q, J=7.2 Hz), 6.35 (1H, d, J=16.1 Hz), 6.92 (1H, d, J=8.8 Hz), 7.39 (1H,dd, J=8.8, 2.4 Hz), 7.61 (1H, d, J=2.4 Hz), 7.95 (1H, d, J=16.1 Hz).

IR (neat) 1715, 1634, 1481, 1314, 1175, 912, 743 cm⁻¹

REFERENCE EXAMPLE 65

Under an argon atmosphere, a mixture of ethyl(2E)-[5-bromo-2-[methyl(propyl)amino]phenyl]acrylate (1.869 g),4-(2-butoxyethoxy)phenylboric acid (1.73 g) and potassium carbonate(1.54 g) in toluene (60 ml), ethanol (6 ml) and water (6 ml) was stirredfor 0.5 hour at room temperature. Tetrakis(triphenylphosphine)palladium(0.19 g) was added to the reaction system, and the mixture was heatedunder reflux for 6 hours. After cooling to room temperature, theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with water and saturated brine, and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasseparated and purified by column chromatography (ethyl acetate:hexane1:19→1:9) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-[methyl(propyl)amino]-1,1′-biphenyl-3-yl]acrylate(2.22 g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.90 (3H, t, J=7.3 Hz), 0.93 (3H, t, J=7.2Hz), 1.28-1.46 (5H, m), 1.55-1.69 (4H, m), 2.76 (3H, s), 2.91 (2H, t,J=7.5 Hz), 3.56 (2H, t, J=6.8 Hz), 3.81 (2H, t, J=5.0 Hz), 4.17 (2H, t,J=5.0 Hz), 4.28 (2H, q, J=7.1 Hz), 6.45 (1H, d, J=16.3 Hz), 6.99 (2H, d,J=8.8 Hz), 7.11 (1H, d, J=8.4 Hz), 7.44-7.53 (3H, m), 7.69 (1H, d, J=2.2Hz), 8.11 (1H, d, J=16.3 Hz).

IR (neat) 1709, 1632, 1607, 1489, 1302, 1273, 1246, 1177, 912, 821, 739cm⁻¹

REFERENCE EXAMPLE 66

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-[methyl(propyl)amino]-1,1′-biphenyl-3-yl]acrylate(2.22 g) in ethanol (20 ml) and THF (10 ml) was added a 1 N aqueoussodium hydroxide solution (10.0 ml) at room temperature, and the mixturewas stirred at 65° C. for 6 hours. 1 N Hydrochloric acid (10.0 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the precipitated crystals were collected byfiltration. The crystals were washed with diisopropyl ether and hexaneto give(2E)-3-[4′-(2-butoxyethoxy)-4-[methyl(propyl)amino]-1,1′-biphenyl-3-yl]acrylicacid (1.52 g) as yellow crystals.

m.p. 95-97° C.

¹H-NMR (200 MHz, CDCl₃) δ 0.90 (3H, t, J=7.3 Hz), 0.93 (3H, t, J=7.3Hz), 1.29-1.49 (2H, m), 1.55-1.68 (4H, m), 2.78 (3H, s), 2.93 (2H, t,J=7.5 Hz), 3.56 (2H, t, J=6.6 Hz) 3.81 (2H, t, J=5.0 Hz), 4.17 (2H, t,J=5.0 Hz), 6.47 (1H, d, J=16.1 Hz), 7.00 (2H, d, J=8.6 Hz), 7.12 (1H, d,J=8.4 Hz), 7.47-7.55 (3H, m), 7.71 (1H, d, J=2.6 Hz), 8.22 (1H, d,J=16.1 Hz).

Elementary analysis C₂₅H₃₃NO₄, Calcd. C, 72.96; H, 8.08; N, 3.40. Found.C, 72.70; H, 8.16; N, 3.37.

REFERENCE EXAMPLE 67

A mixture of 5-bromo-2-fluorobenzaldehyde (1.30 g), 3-methylpiperidine(1.13 ml) and potassium carbonate (1.77 g) in DMF (20 ml) was stirred at80° C. for 2 days. Water was added to the reaction system, and theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with water and saturated brine, and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasseparated and purified by column chromatography (ethyl acetate:hexane1:49) to give 5-bromo-2-(3-methylpiperidin-1-yl)benzaldehyde (1.47 g) asa yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, d, J=6.0 Hz), 0.96-1.15 (1H, m),1.68-1.98 (4H, m), 2.49 (1H, dd, J=11.8, 10.2 Hz), 2.67-2.88 (1H, m),3.09-3.25 (2H, m), 6.98 (1H, d, J=8.8 Hz), 7.57 (1H, dd, J=8.8, 2.6 Hz),7.89 (1H, d, J=2.6 Hz), 10.19 (1H, s).

IR (neat) 1682, 1586, 1480, 1383, 1231, 1177, 912, 743 cm⁻¹

REFERENCE EXAMPLE 68

To a suspension of sodium hydride (60%, 0.27 g) in toluene (10 ml) wasadded dropwise a solution of ethyl diethylphosphonoacetate (1.34 ml) intoluene (10 ml) at 0° C. under an argon atmosphere. After stirring at 0°C. for 30 minutes, a solution of5-bromo-2-(3-methylpiperidin-1-yl)benzaldehyde (1.47 g) in toluene (20ml) was added thereto, and the resulting mixture was heated under refluxfor 3 hours. Water was added to the reaction system, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:49→1:19) togive ethyl (2E)-3-[5-bromo-2-(3-methylpiperidin-1-yl)phenyl]acrylate(1.78 g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, d, J=6.6 Hz), 0.95-1.14 (1H, m),1.34 (3H, t, J=7.2 Hz), 1.68-1.98 (4H, m), 2.27-2.37 (1H, m), 2.49-2.66(1H, m), 2.97-3.12 (2H, m), 4.27 (2H, q, J=7.2 Hz), 6.37 (1H, d, J=16.1Hz), 6.70 (1H, d, J=8.6 Hz), 7.40 (1H, dd, J=8.6, 2.4 Hz), 7.62 (1H, d,J=2.4 Hz), 7.94 (1H, d, J=16.1 Hz).

REFERENCE EXAMPLE 69

Under an argon atmosphere, a mixture of ethyl(2E)-3-[5-bromo-2-(3-methylpiperidin-1-yl)phenyl]acrylate (1.78 g),4-(2-butoxyethoxy)phenylboric acid (1.56 g) and potassium carbonate(1.40 g) in toluene (50 ml), ethanol (5 ml) and water (5 ml) was stirredfor 30 minutes at room temperature.Tetrakis(triphenylphosphine)palladium (0.17 g) was added to the reactionsystem, and the mixture was heated under reflux for 6 hours. Aftercooling to room temperature, the resulting mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:29→1:19→1:9) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]acrylate(2.15 g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 0.95 (3H, d, J=6.6Hz), 1.28-1.48 (5H, m), 1.53-2.04 (6H, m), 2.33-2.43 (2H, m), 2.52-2.73(1H, m), 3.03-3.17 (2H, m), 3.56 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=4.9Hz), 4.17 (2H, t, J=4.9 Hz), 4.28 (2H, q, J=7.2 Hz), 6.47 (1H, d, J=16.3Hz), 6.99 (2H, d, J=8.8 Hz), 7.08 (1H, d, J=8.4 Hz), 7.44-7.54 (3H, m),7.70 (1H, d, J=2.2 Hz), 8.09 (1H, d, J=16.3 Hz).

IR (neat) 1711, 1632, 1607, 1489, 1248, 1235, 1177, 912, 821, 743 cm⁻¹

REFERENCE EXAMPLE 70

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]acrylate(2.17 g) in ethanol (20 ml) and THF (10 ml) was added a 1 N aqueoussodium hydroxide solution (10.0 ml) at room temperature, and the mixturewas stirred at 65° C. for 4 hours. 1 N Hydrochloric acid (10.0 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:4→1:2) to give(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]acrylicacid (1.48 g) as yellow crystals.

m.p. 125-127° C.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.4 Hz), 0.95 (3H, d, J=6.6Hz), 1.30-2.02 (9H, m), 2.33-2.44 (1H, m), 2.52-2.78 (1H, m), 3.03-3.18(2H, m), 3.56 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=4.9 Hz), 4.17 (2H, t,J=4.9 Hz), 6.49 (1H, d, J=16.2 Hz), 6.99 (2H, d, J=8.6 Hz), 7.09 (1H, d,J=8.6 Hz), 7.46-7.56 (3H, m), 7.71 (1H, d, J=2.2 Hz), 8.19 (1H, d,J=16.2 Hz).

Elementary analysis C₂₇H₃₅NO4, Calcd. C, 74.11; H, 8.06; N, 3.20. Found.C, 74.41; H, 7.94; N, 2.89.

REFERENCE EXAMPLE 71

A mixture of 5-bromo-2-fluorobenzaldehyde (1.50 g), 2-methylpiperidine(1.74 ml) and sodium carbonate (1.57 g) in DMSO (20 ml) and water (5 ml)was stirred at 110° C. for 2.5 days. Water was added to the reactionsystem, and the resulting mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by column chromatography (ethylacetate:hexane 1:49) to give5-bromo-2-(2-methylpiperidin-1-yl)benzaldehyde (1.365 g) as a yellowoily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.91 (3H, d, J=6.2 Hz), 1.37-1.59 (2H, m),1.63-1.97 (4H, m), 2.72-2.86 (1H, m), 2.99-3.25 (2H, m), 7.11 (1H, d,J=8.6 Hz), 7.62 (1H, dd, J=8.6, 2.6 Hz), 7.92 (1H, d, J=2.6 Hz), 10.40(1H, s).

IR (neat) 1682, 1584, 1474, 1370, 1256, 1175, 876 cm⁻¹

REFERENCE EXAMPLE 72

To a suspension of sodium hydride (60%, 0.23 g) in toluene (10 ml) wasadded dropwise a solution of ethyl diethylphosphonoacetate (1.15 ml) intoluene (10 ml) at 0° C. under an argon atmosphere. After stirring at 0°C. for 30 minutes, a solution of5-bromo-2-(2-methylpiperidin-1-yl)benzaldehyde (1.365 g) in toluene (20ml) was added thereto, and the resulting mixture was heated under refluxfor 2 hours. Water was added to the reaction system, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:49→1:19) togive ethyl (2E)-3-[5-bromo-2-(2-methylpiperidin-1-yl)phenyl]acrylate(1.666 g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.85 (3H, d, J=6.3 Hz), 1.34 (3H, t, J=7.1Hz), 1.41-1.54 (2H, m), 1.59-1.94 (4H, m), 2.54-2.62 (1H, m), 2.89-2.97(1H, m), 3.02-3.12 (1H, m), 4.21-4.32 (2H, m), 6.37 (1H, d, J=16.2 Hz),6.98 (1H, d, J=8.6 Hz), 7.41 (1H, dd, J=8.6, 2.4 Hz), 7.66 (1H, d, J=2.4Hz), 8.11 (1H, d, J=16.2 Hz).

IR (neat) 1713, 1634, 1478, 1312, 1179, 912, 743 cm⁻¹

REFERENCE EXAMPLE 73

Under an argon atmosphere, a mixture of ethyl(2E)-3-[5-bromo-2-(2-methylpiperidin-1-yl)phenyl]acrylate (1.666 g),4-(2-butoxyethoxy)phenylboric acid (1.35 g) and potassium carbonate(1.31 g) in toluene (50 ml), ethanol (5 ml) and water (5 ml) was stirredfor 30 minutes at room temperature.Tetrakis(triphenylphosphine)palladium (0.16 g) was added to the reactionsystem, and the mixture was heated under reflux for 6 hours. Aftercooling to room temperature, the resulting mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:19→1:9) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(2-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]acrylate(2.137 g) as yellow crystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.90 (3H, d, J=6.2 Hz), 0.93 (3H, t, J=7.1Hz), 1.28-1.98 (13H, m), 2.56-2.72 (1H, m), 2.91-3.21 (2H, m), 3.56 (2H,t, J=6.6 Hz), 3.81 (2H, t, J=4.9 Hz), 4.14-4.33 (4H, m), 6.49 (1H, d,J=16.2 Hz), 6.99 (2H, d, J=8.8 Hz), 7.16 (1H, d, J=8.0 Hz), 7.17-7.55(3H, m), 7.74 (1H, d, J=2.2 Hz), 8.27 (1H, d, J=16.2 Hz).

IR (neat) 1711, 1632, 1609, 1485, 1283, 1246, 1175, 1125, 912, 742 cm⁻¹

REFERENCE EXAMPLE 74

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(2-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]acrylate(2.137 g) in ethanol (20 ml) and THF (10 ml) was added a 1 N aqueoussodium hydroxide solution (10.0 ml) at room temperature, and the mixturewas stirred at 60° C. for 4 hours. 1 N Hydrochloric acid (10.0 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the precipitated crystals were collected byfiltration. The crystals were washed with diisopropyl ether and hexaneto give(2E)-3-[4′-(2-butoxyethoxy)-4-(2-methylpiperidin-1-yl)-1,1′-biphenyl-3-yl]acrylicacid (1.26 g) as yellow crystals.

m.p. 106-108° C.

¹H-NMR (200 MHz, CDCl₃) δ 0.90-0.97 (6H, m), 1.29-2.01 (10H, m),2.59-2.75 (1H, m), 2.93-3.24 (2H, m), 3.56 (2H, t, J=6.6 Hz), 3.82 (2H,t, J=5.0 Hz), 4.17 (2H, t, J=5.0 Hz), 6.51 (1H, d, J=16.3 Hz), 7.00 (2H,d, J=8.8 Hz), 7.19 (1H, d, J=8.4 Hz), 7.49-7.58 (3H, m), 7.76 (1H, d,J=2.4 Hz), 8.38 (1H, d, J=16.3 Hz).

Elementary analysis C₂₇H₃₅NO₄, Calcd. C, 74.11; H, 8.06; N, 3.20. Found.C, 74.08; H, 8.08; N, 3.04.

REFERENCE EXAMPLE 75

A mixture of 5-bromo-2-fluorobenzaldehyde (2.50 g), 3-methylpiperidine(3.32 g) and potassium carbonate (5.1 g) in DMF (30 ml) was stirred at80° C. for 2 days. Water was added to the reaction system, and theresulting mixture was extracted with ethyl acetate. The organic layerwas washed with water and saturated brine, and dried over magnesiumsulfate. After concentration under reduced pressure, the residue wasseparated and purified by column chromatography (ethyl acetate:hexane1:49→1:19) to give 5-bromo-2-(3-methylpyrrolidin-1-yl)benzaldehyde (2.37g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.13 (3H, d, J=6.6 Hz), 1.53-1.72 (1H, m),2.05-2.19 (1H, m), 2.23-2.44 (1H, m), 3.02-3.11 (1H, m), 3.25-3.57 (3H,m), 6.69 (1H, d, J=9.2 Hz), 7.41 (1H, dd, J=9.2, 2.6 Hz), 7.79 (1H, d,J=2.6 Hz), 10.02 (1H, s).

REFERENCE EXAMPLE 76

To a suspension of sodium hydride (60%, 0.21 g) in toluene (10 ml) wasadded dropwise a solution of ethyl diethylphosphonoacetate (1.04 ml) intoluene (10 ml) at 0° C. under an argon atmosphere. After stirring at 0°C. for 30 minutes, a solution of5-bromo-2-(3-methylpyrrolidin-1-yl)benzaldehyde (1.17 g) in toluene (10ml) was added thereto, and the resulting mixture was heated under refluxfor 2 hours. Water was added to the reaction system, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:19) to giveethyl (2E)-3-[5-bromo-2-(3-methylpyrrolidin-1-yl)phenyl]acrylate (1.32g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.10 (3H, d, J=6.6 Hz), 1.33 (3H, t, J=7.1Hz), 1.42-1.66 (1H, m), 1.99-2.15 (1H, m), 2.23-2.43 (1H, m), 2.90-2.98(1H, m), 3.21-3.47 (3H, m), 4.25 (2H, q, J=7.1 Hz), 6.20 (1H, d, J=16.0Hz), 6.67 (1H, d, J=8.8 Hz), 7.28 (1H, dd, J=8.8, 2.6 Hz), 7.48 (1H, d,J=2.6 Hz), 7.93 (1H, d, J=16.0 Hz).

IR (neat) 1713, 1626, 1474, 1316, 1175, 912, 741 cm⁻¹

REFERENCE EXAMPLE 77

Under an argon atmosphere, a mixture of ethyl(2E)-3-[5-bromo-2-(3-methylpyrrolidin-1-yl)phenyl]acrylate (1.32 g),4-(2-butoxyethoxy)phenylboric acid (1.11 g) and potassium carbonate(1.08 g) in toluene (40 ml), ethanol (4 ml) and water (4 ml) was stirredfor 30 minutes at room temperature.Tetrakis(triphenylphosphine)palladium (0.13 g) was added to the reactionsystem, and the mixture was heated under reflux for 6 hours. Aftercooling to room temperature, the resulting mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:19→1:9) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]acrylate(761 mg) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.3 Hz), 1.12 (3H, d, J=6.6Hz), 1.28-1.48 (5H, m), 1.51-1.68 (3H, m), 1.99-2.20 (1H, m), 2.24-2.47(1H, m), 2.97-3.05 (1H, m), 3.26-3.59 (5H, m), 3.81 (2H, t, J=4.9 Hz),4.16 (2H, t, J=4.9 Hz), 4.26 (2H, q, J=7.2 Hz), 6.30 (1H, d, J=15.8 Hz),6.87 (1H, d, J=8.4 Hz), 6.97 (2H, d, J=8.6 Hz), 7.41-7.48 (3H, m), 7.59(1H, d, J=2.6 Hz), 8.08 (1H, d, J=15.8 Hz).

IR (neat) 1709, 1607, 1495, 1478, 1300, 1246, 1175, 912, 743 cm⁻¹

REFERENCE EXAMPLE 78

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]acrylate(761 mg) in ethanol (10 ml) and THF (5 ml) was added a 1 N aqueoussodium hydroxide solution (4.0 ml) at room temperature, and the mixturewas stirred at 65° C. for 6 hours. 1 N Hydrochloric acid (4.0 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the precipitated crystals were collected byfiltration. The crystals were washed with diisopropyl ether and hexaneto give(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]acrylicacid (596 mg) as yellow crystals.

m.p. 136-139° C.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.3 Hz), 1.13 (3H, d, J=6.6Hz), 1.31-1.49 (2H, m), 1.53-1.68 (3H, m), 2.02-2.19 (1H, m), 2.25-2.47(1H, m), 2.99-3.07 (1H, m), 3.28-3.59 (5H, m), 3.81 (2H, t, J=4.9 Hz),4.16 (2H, t, J=4.9 Hz), 6.30 (1H, d, J=15.8 Hz), 6.88 (1H, d, J=8.8 Hz),6.98 (2H, d, J=8.6 Hz), 7.43-7.49 (3H, m), 7.61 (1H, d, J=2.2 Hz), 8.19(1H, d, J=15.8 Hz).

REFERENCE EXAMPLE 79

To a suspension of sodium hydride (60%, 0.21 g) in toluene (10 ml) wasadded dropwise a solution of ethyl 2-(diethylphosphono)propionate (1.28g) in toluene (10 ml) at 0° C. under an argon atmosphere. After stirringat 0° C. for 1 hour, a solution of5-bromo-2-(3-methylpyrrolidin-1-yl)benzaldehyde (1.20 g) in toluene (20ml) was added thereto, and the resulting mixture was heated under refluxfor 6 hours. Water was added to the reaction system, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:19→1:9) togive ethyl(2E)-3-[5-bromo-2-(3-methylpyrrolidin-1-yl)phenyl]-2-methylacrylate(1.49 g) as yellow crystals.

¹H-NMR (200 MHz, CDCl₃) δ 1.08 (3H, d, J=7.0 Hz), 1.34 (3H, t, J=7.1Hz), 1.44-1.62 (1H, m), 1.95-2.10 (4H, m), 2.19-2.39 (1H, m), 2.80-2.89(1H, m), 3.10-3.38 (3H, m), 4.26 (2H, q, J=7.1 Hz), 6.64 (1H, d, J=8.8Hz), 7.20-7.28 (2H, m), 7.67 (1H, s).

REFERENCE EXAMPLE 80

Under an argon atmosphere, a mixture of ethyl(2E)-3-[5-bromo-2-(3-methylpyrrolidin-1-yl)phenyl]-2-methylacrylate(1.49 g), 4-(2-butoxyethoxy)phenylboric acid (1.21 g) and potassiumcarbonate (1.17 g) in toluene (40 ml), ethanol (4 ml) and water (4 ml)was stirred for 30 minutes at room temperature.Tetrakis(triphenylphosphine)palladium (0.15 g) was added to the reactionsystem, and the mixture was heated under reflux for 6 hours. Aftercooling to room temperature, the resulting mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:19→1:9) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylate(1.4467 g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.1 Hz), 1.10 (3H, d, J=6.6Hz), 1.27-1.48 (6H, m), 1.54-1.68 (2H, m), 1.96-2.15 (4H, m), 2.21-2.45(1H, m), 2.88-2.96 (1H, m), 3.17-3.45 (3H, m), 3.55 (2H, t, J=6.6 Hz),3.80 (2H, t, J=5.0 Hz), 4.15 (2H, t, J=5.0 Hz), 4.27 (2H, q, J=7.2 Hz),6.83 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8 Hz), 7.32-7.49 (4H, m), 7.83(1H, s)

REFERENCE EXAMPLE 81

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylate(1.45 g) in ethanol (20 ml) and THF (10 ml) was added a 1 N aqueoussodium hydroxide solution (7.5 ml) at room temperature, and the mixturewas stirred at 65° C. for 4 hours. 1 N Hydrochloric acid (7.5 ml) wasadded thereto at 0° C., and the resulting mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the precipitated crystals were collected byfiltration. The crystals were washed with diisopropyl ether and hexaneto give(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylicacid (1.057 g) as yellow crystals.

m.p. 139-141° C.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.3 Hz), 1.11 (3H, d, J=6.6Hz), 1.30-1.69 (5H, m), 1.95-2.16 (4H, m), 2.21-2.45 (1H, m), 2.89-2.98(1H, m), 3.21-3.48 (3H, m), 3.55 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=4.8Hz), 4.16 (2H, t, J=4.8 Hz), 6.85 (1H, d, J=8.8 Hz), 6.97 (2H, d, J=8.8Hz), 7.35-7.47 (4H, m), 7.98 (1H, s).

REFERENCE EXAMPLE 82

A mixture of 5-bromo-2-fluorobenzaldehyde (3.0 g), 3-pyrrolidinol (2.57g) and sodium carbonate (3.12 g) in DMSO (30 ml) and water (6 ml) wasstirred at 100° C. for 4 hours, which was extracted with ethyl acetate.Next, the organic layer was washed with water and saturated brine, anddried over magnesium sulfate. After concentration under reducedpressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:1→1:2) to give5-bromo-2-(3-hydroxypyrrolidin-1-yl)benzaldehyde (3.53 g) as a yellowoily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.70 (1H, d, J=4.0 Hz), 1.99-2.28 (2H, m),2.99-3.08 (1H, m), 3.30-3.41 (1H, m), 3.64-3.77 (2H, m), 4.55-4.66 (1H,m), 6.75 (1H, d, J=9.1 Hz), 7.46 (1H, dd, J=9.1, 2.5 Hz), 7.79 (1H, d,J=2.5 Hz), 9.99 (1H, s).

IR (neat) 3347, 1661, 1593, 1489, 1472, 1408, 1179, 912, 741 cm⁻¹

REFERENCE EXAMPLE 83

To a solution of 5-bromo-2-(3-hydroxypyrrolidin-1-yl)benzaldehyde (2.17g) in DMF (20 ml) was added sodium hydride (60%, 0.36 g) at 0° C., andthe mixture was stirred at 0° C. for 1 hour. To the reaction system wasadded iodomethane (0.75 ml), and the mixture was stirred at roomtemperature for 14 hours. Water was added to the reaction system, andthe resulting mixture was extracted with ethyl acetate. The organiclayer was washed with water and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by column chromatography (ethylacetate:hexane 1:19→1:9→1:4) to give5-bromo-2-(3-methoxypyrrolidin-1-yl)benzaldehyde (1.0275 g) as a yellowoily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.97-2.25 (2H, m), 3.04-3.13 (1H, m),3.26-3.43 (4H, m), 3.51-3.59 (1H, m), 3.68 (1H, dd, J=11.6, 4.6 Hz),4.02-4.10 (1H, m), 6.73 (1H, d, J=8.8 Hz), 7.44 (1H, dd, J=8.8, 2.6 Hz),7.79 (1H, d, J=2.6 Hz), 10.00 (1H, s).

IR (neat) 1676, 1593, 1489, 1470, 1406, 1177, 1103, 912, 743 cm⁻¹

REFERENCE EXAMPLE 84

Under an argon atmosphere, to a suspension of sodium hydride (60%, 0.17g) in toluene (10 ml), was added dropwise a solution of ethyl2-(diethylphosphono)propionate (1.03 g) in toluene (10 ml) at 0° C.After stirring at 0° C. for 301 hours, a solution of5-bromo-2-(3-methoxypyrrolidin-1-yl)benzaldehyde (1.0275 g) in toluene(20 ml) was added thereto, and the mixture was heated under reflux for3.5 hours. To the reaction system was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:4) to giveethyl(2E)-3-[5-bromo-2-(3-methoxypyrrolidin-1-yl)phenyl]-2-methylacrylate(1.199 g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.34 (3H, t, J=7.1 Hz), 1.99 (3H, d, J=1.4Hz), 2.01-2.09 (2H, m), 3.10-3.23 (2H, m), 3.32-3.46 (5H, m), 3.94-4.04(1H, m), 4.26 (2H, q, J=7.1 Hz), 6.67 (1H, d, J=8.8 Hz), 7.22-7.30 (2H,m), 7.66 (1H, s).

IR (neat) 1705, 1474, 1273, 912, 743 cm⁻¹

REFERENCE EXAMPLE 85

Under an argon atmosphere, a mixture of ethyl(2E)-3-[5-bromo-2-(3-methoxypyrrolidin-1-yl)phenyl]-2-methylacrylate(1.199 g), 4-(2-butoxyethoxy)phenylboric acid (0.93 g) and potassiumcarbonate (0.90 g) in toluene (30 ml), ethanol (3 ml) and water (3 ml)was stirred for 30 minutes at room temperature.Tetrakis(triphenylphosphine)palladium (0.11 g) was added to the reactionsystem, and the mixture was heated under reflux for 6 hours. Aftercooling to room temperature, the reaction mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:9→1:4) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methoxypyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylate(1.177 g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.4 Hz), 1.32-1.45 (5H, m),1.51-1.65 (2H, m), 1.97-2.13 (5H, m), 3.19-3.28 (2H, m), 3.33 (3H, s),3.36-3.57 (4H, m), 3.80 (2H, t, J=5.0 Hz), 3.96-4.05 (1H, m), 4.15 (2H,t, J=5.0 Hz), 4.27 (2H, q, J=7.1 Hz), 6.87 (1H, d, J=8.1 Hz), 6.97 (2H,d, J=8.7 Hz), 7.33 (1H, d, J=2.4 Hz), 7.39-7.46 (3H, m), 7.81 (1H, s)

IR (neat) 1705, 1605, 1495, 1271, 1244, 1113, 912, 743 cm⁻¹

REFERENCE EXAMPLE 86

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methoxypyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylate(1.177 g) in ethanol (10 ml) and THF (5 ml), was added a 1 N aqueoussodium hydroxide solution (5.0 ml) at room temperature. After stirringat 65° C. for 6 hours, 1 N hydrochloric acid (5.0 ml) was added theretoat 0° C., and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theprecipitated crystals were collected by filtration. The crystals werewashed with diisopropyl ether and hexane to give(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methoxypyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylicacid (967 mg) as yellow crystals.

m.p. 144-145° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.33-1.45 (2H, m),1.56-1.65 (2H, m), 2.02-2.12 (5H, m), 3.18-3.29 (2H, m), 3.34 (3H, s),3.40-3.57 (4H, m), 3.80 (2H, t, J=5.0 Hz), 3.99-4.06 (1H, m), 4.15 (2H,t, J=5.0 Hz), 6.88 (1H, d, J=8.7 Hz), 6.96 (2H, d, J=8.7 Hz), 7.35 (1H,d, J=1.8 Hz), 7.39-7.45 (3H, m), 7.94 (1H, s).

Elementary analysis C₂₇H₃₅NO5, Calcd. C, 71.50; H, 7.78; N, 3.09. Found.C, 71.63; H, 7.78; N, 3.03.

REFERENCE EXAMPLE 87

To a solution of 5-bromo-2-(3-hydroxypyrrolidin-1-yl)benzaldehyde (3.53g) in pyridine (20 ml), was added acetic anhydride (2.5 ml) at 0° C. Themixture was stirred for 4 days at room temperature and concentratedunder reduced pressure. Water was added to the residue, and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:9→1:4→1:2) togive 5-bromo-2-(3-acetoxypyrrolidin-1-yl)benzaldehyde (4.15 g) as ayellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 2.04 (3H, s), 2.13-2.31 (2H, m), 3.06-3.13(1H, m), 3.30-3.40 (1H, m), 3.59-3.72 (1H, m), 3.82 (1H, dd, J=12.1, 4.7Hz), 5.31-5.44 (1H, m), 6.74 (1H, d, J=8.8 Hz), 7.48 (1H, dd, J=8.8, 2.6Hz), 7.80 (1H, d, J=2.6 Hz), 9.98 (1H, s).

REFERENCE EXAMPLE 88

Under an argon atmosphere, a mixture of5-bromo-2-(3-acetoxypyrrolidin-1-yl)benzaldehyde (1.0 g) and tert-butyl2-(triphenylphosphoranylidene)propionate (1.88 g) in toluene (10 ml) washeated under reflux for 2 hours. To the reaction system was added water,and the mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, and dried over magnesium sulfate.After concentration under reduced pressure, the residue was separatedand purified by column chromatography (ethyl acetate:hexane 1:9) to givetert-butyl(2E)-3-[2-[3-(acetoxy)pyrrolidin-1-yl]-5-bromophenyl]-2-methylacrylate(1.21 g) as a pale yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.53 (9H, s), 1.95 (3H, d, J=1.2 Hz),1.98-2.31 (5H, m), 3.09-3.28 (2H, m), 3.36-3.58 (2H, m), 5.25-5.36 (1H,m), 6.68 (1H, d, J=8.6 Hz), 7.26-7.31 (2H, m), 7.54 (1H, s).

REFERENCE EXAMPLE 89

Under an argon atmosphere, a mixture of tert-butyl(2E)-3-[2-[3-(acetoxy)pyrrolidin-1-yl]-5-bromophenyl]-2-methylacrylate(5.37 g), 4-(2-butoxyethoxy)phenylboric acid (3.92 g) and potassiumcarbonate (3.50 g) in toluene (130 ml), ethanol (13 ml) and water (13ml) was stirred for 30 minutes at room temperature.Tetrakis(triphenylphosphine)palladium (0.44 g) was added to the reactionsystem, and the mixture was heated under reflux for 6 hours. Aftercooling to room temperature, the mixture was extracted with ethylacetate. The organic layer was washed with water and saturated brine,and dried over magnesium sulfate. After concentration under reducedpressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:9→1:4) to give tert-butyl(2E)-3-[4-[3-(acetoxy)pyrrolidin-1-yl-4′-(2-butoxyethoxy)]-1,1′-biphenyl-3-yl]acrylate(5.66 g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.30-1.41 (2H, m),1.55-1.66 (11H, m), 2.01-2.38 (8H, m), 3.18-3.65 (6H, m), 3.80 (2H, t,J=4.9 Hz), 4.15 (2H, t, J=4.9 Hz), 5.26-5.38 (1H, m), 6.87 (1H, d, J=8.4Hz), 6.97 (2H, d, J=8.8 Hz), 7.35-7.47 (4H, m), 7.69 (1H, s).

IR (neat) 1740, 1703, 1493, 1478, 1277, 1246, 1123 cm⁻¹

REFERENCE EXAMPLE 90

To a solution of tert-butyl(2E)-3-[4-[3-(acetoxy)pyrrolidin-1-yl-4′-(2-butoxyethoxy)]-1,1′-biphenyl-3-yl]acrylate(2.0 g) in ethyl acetate (20 ml) was added 4 N hydrochloric acid (inethyl acetate, 5.0 ml) at 0° C. After stirring for 14 hours at roomtemperature, 4 N hydrochloric acid (in ethyl acetate, 10.0 ml) wasfurther added thereto, and the mixture was stirred for 1 hour. To thereaction system was added water, and the mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the precipitated crystals were collected byfiltration. The crystals were washed with diisopropyl ether to give(2E)-3-[4-[3-(acetoxy)pyrrolidin-1-yl-4′-(2-butoxyethoxy)]-1,1′-biphenyl-3-yl]acrylicacid (1.41 g) as yellow crystals.

m.p. 135-137° C.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.28-1.47 (2H, m),1.55-1.69 (2H, m), 2.07-2.33 (8H, m), 3.18-3.34 (2H, m), 3.42-3.64 (4H,m), 3.80 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0 Hz), 5.27-5.38 (1H, m),6.90 (1H, d, J=8.4 Hz), 6.98 (2H, d, J=8.8 Hz), 7.38-7.47 (4H, m), 7.94(1H, s).

REFERENCE EXAMPLE 91

A mixture of 5-bromo-2-fluorobenzonitrile (1.0 g), pyrazole (0.34 g) andpotassium carbonate (0.76 g) in DMSO (10 ml) was stirred for 6 hours at100° C. To the reaction system was added water, and the mixture wasextracted with ethyl acetate. The organic layer was washed with waterand saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the precipitated crystals werecollected by filtration. The crystals were washed with diisopropyl etherand hexane to give 5-bromo-2-(1H-pyrazol-1-yl)benzonitrile (1.048 g) ascolorless crystals.

¹H-NMR (200 MHz, CDCl₃) δ 6.56 (1H, dd, J=2.4, 2.1 Hz), 7.70 (1H, d,J=8.7 Hz), 7.79-7.83 (2H, m), 7.89 (1H, d, J=2.1 Hz), 8.13 (1H, d, J=2.4Hz).

IR (KBr) 2232, 1526, 1491, 1399, 934, 750 cm⁻¹

REFERENCE EXAMPLE 92

Under an argon atmosphere, a mixture of5-bromo-2-(1H-pyrazol-1-yl)benzonitrile (2.50 g),4-(2-butoxyethoxy)phenylboric acid (2.88 g) and potassium carbonate(2.79 g) in toluene (100 ml), ethanol (10 ml) and water (10 ml) wasstirred for 30 minutes at room temperature.Tetrakis(triphenylphosphine)palladium (0.35 g) was added to the reactionsystem, and the mixture was heated under reflux for 7 hours. Aftercooling to room temperature, the reaction mixture was extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, and dried over magnesium sulfate. After concentration underreduced pressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:4) to give4′-(2-butoxyethoxy)-4-(1H-pyrazol-1-yl)-1,1′-biphenyl-3-carbonitrile(3.25 g) as a pale yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.94 (3H, t, J=7.2 Hz), 1.30-1.50 (2H, m),1.54-1.69 (2H, m), 3.56 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=5.0 Hz), 4.19(2H, t, J=5.0 Hz), 6.56 (1H, t, J=2.6 Hz), 7.05 (2H, d, J=9.0 Hz), 7.53(2H, d, J=9.0 Hz), 7.80-7.94 (4H, m), 8.17 (1H, d, J=2.6 Hz).

IR (neat) 2230, 1609, 1518, 1499, 1397, 1252, 1125, 936, 910, 826, 737cm⁻¹

REFERENCE EXAMPLE 93

Under an argon atmosphere, to a solution of4′-(2-butoxyethoxy)-4-(1H-pyrazol-1-yl)-1,1′-biphenyl-3-carbonitrile(3.25 g) in toluene (100 ml) was added dropwise diisobutylaluminumhydride (in 1.0 M toluene, 14.0 ml) at 0° C. After stirring for 2 hoursat room temperature, diisobutylaluminum hydride (in 1.0 M toluene, 9.0ml) was added dropwise at room temperature. After stirring the mixturefor 30 minutes at room temperature, an aqueous ammonium chloridesolution was added thereto. The precipitates were removed by filtration,and the filtrate was extracted with ethyl acetate. The organic layer waswashed with saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:4→1:3→1:2) togive4′-(2-butoxyethoxy)-4-(1H-pyrazol-1-yl)-1,1′-biphenyl-3-carbaldehyde(788 mg) as a pale yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.94 (3H, t, J=7.1 Hz), 1.30-1.48 (2H, m),1.51-1.68 (2H, m), 3.56 (2H, t, J=6.6 Hz), 3.82 (2H, t, J=5.0 Hz), 4.19(2H, t, J=5.0 Hz), 6.57 (1H, t, J=2.2 Hz), 7.04 (2H, d, J=8.8 Hz),7.53-7.61 (3H, m), 7.82-7.89 (3H, m), 8.20 (1H, d, J=2.2 Hz), 10.08 (1H,s).

IR (neat) 1688, 1609, 1512, 1397, 1252, 1184, 1128, 937, 828 cm⁻¹

REFERENCE EXAMPLE 94

Under an argon atmosphere, to a suspension of sodium hydride (60%, 0.11g) in toluene (10 ml) was added dropwise a solution of ethyl2-(diethylphosphono)propionate (0.67 g) in toluene (10 ml) at 0° C.After stirring for 1 hour at 0° C., a solution of4′-(2-butoxyethoxy)-4-(1H-pyrazol-1-yl)-1,1′-biphenyl-3-carbaldehyde(788 mg) in toluene (10 ml) was added thereto, and the mixture washeated under reflux for 4 hours. To the reaction system was added water,and the mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, and dried over magnesium sulfate.After concentration under reduced pressure, the residue was separatedand purified by column chromatography (ethyl acetate:hexane 1:4) to giveethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(1H-pyrazol-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylate(842 g) as pale yellow crystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.94 (3H, t, J=7.4 Hz), 1.26-1.50 (5H, m),1.55-1.69 (2H, m), 2.03 (3H, d, J=1.6 Hz), 3.56 (2H, t, J=6.6 Hz), 3.82(2H, t, J=4.9 Hz), 4.16-4.29 (4H, m), 6.45 (1H, t, J=1.8 Hz), 7.03 (2H,d, J=8.8 Hz), 7.52-7.58 (4H, m), 7.63-7.65 (3H, m), 7.74 (1H, d, J=1.8Hz).

IR (neat) 1709, 1609, 1514, 1493, 1399, 1271, 1246, 1115, 912, 745 cm⁻¹

REFERENCE EXAMPLE 95

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(1H-pyrazol-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylate(790 mg) in ethanol (20 ml) and THF (10 ml) was added a 1 N aqueoussodium hydroxide solution (3.5 ml) at room temperature. After stirringfor 4 hours at 50° C., 1 N hydrochloric acid (3.5 ml) was added theretoat 0° C., and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theprecipitated crystals were collected by filtration. The crystals werewashed with diisopropyl ether to give(2E)-3-[4′-(2-butoxyethoxy)-4-(1H-pyrazol-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylicacid (700 mg) as yellow crystals.

m.p. 132-134° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J=7.4 Hz), 1.34-1.46 (2H, m),1.57-1.66 (2H, m), 2.05 (3H, d, J=1.5 Hz), 3.56 (2H, t, J=6.6 Hz), 3.82(2H, t, J=4.9 Hz), 4.18 (2H, q, J=4.9 Hz), 6.45 (1H, t, J=1.8 Hz), 7.02(2H, d, J=8.7 Hz), 7.52 (2H, d, J=8.7 Hz), 7.58 (1H, s), 7.62-7.66 (4H,m), 7.74 (1H, d, J=1.8 Hz).

REFERENCE EXAMPLE 96

Under an argon atmosphere, to a suspension of sodium hydride (1.44 g) inDMF (150 ml) was added dropwise a solution of1,2,3,4-tetrahydroquinoline (4.0 g) in DMF (20 ml) at 0° C. Afterstirring for 1 hour at 0° C., iodomethane (2.06 ml) was added to thereaction system at 0° C., and the mixture was stirred for 12 hours atroom temperature. To the reaction system was added water, and themixture was extracted with ethyl acetate. The organic layer was washedwith water and saturated brine, and dried over magnesium sulfate. Afterconcentration under reduced pressure, the residue was separated andpurified by column chromatography (ethyl acetate:hexane 1:19) to give1-methyl-1,2,3,4-tetrahydroquinoline (3.64 g) as a colorless oilymaterial.

¹H-NMR (300 MHz, CDCl₃) δ 1.94-2.02 (2H, m), 2.76 (2H, t, J=6.6 Hz),2.88 (3H, s), 3.21 (2H, t, J=5.7 Hz), 6.57-6.62 (2H, m), 6.93-6.96 (1H,m), 7.04-7.25 (1H, m).

REFERENCE EXAMPLE 97

To a solution of 1-methyl-1,2,3,4-tetrahydroquinoline (3.64 g) indichloromethane (50 ml) was added tetrabutylammonium tribromide (11.92g) at 0° C. The mixture was stirred for 30 minutes at 0° C. and for 18hours at room temperature. Water was added to the reaction system, andthe mixture was extracted with dichloromethane. The organic layer waswashed with an aqueous sodium thiosulfate solution and saturated brine,and dried over magnesium sulfate. After concentration under reducedpressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:19) to give6-bromo-1-methyl-1,2,3,4-tetrahydroquinoline (4.65 g) as a pale yellowoily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.89-2.01 (2H, m), 2.73 (2H, t, J=6.4 Hz),2.85 (3H, s), 3.20 (2H, t, J=5.7 Hz), 6.43 (1H, d, J=8.6 Hz), 7.02-7.05(1H, m), 7.10-7.16 (1H, m).

IR (neat) 1501, 1323, 1208, 912, 740 cm⁻¹

REFERENCE EXAMPLE 98

To a solution of 6-bromo-1-methyl-1,2,3,4-tetrahydroquinoline (4.65 g)in DMF (40 ml) was added chloromethylenedimethylammonium chloride (3.95g) at room temperature, and the mixture was stirred for 1 hour at 65° C.The reaction mixture was added to ice water. After neutralization usingpotassium carbonate, the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theresidue was separated and purified by column chromatography (ethylacetate:hexane 1:19→1:9) to give6-bromo-1-methyl-1,2,3,4-tetrahydroquinoline-8-carbaldehyde (2.82 g) asa yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.87-1.99 (2H, m), 2.75 (2H, t, J=6.2 Hz),3.04 (3H, s), 3.27 (2H, t, J=5.6 Hz), 7.20 (1H, d, J=2.6 Hz), 7.63 (1H,d, J=2.6 Hz), 9.94 (1H, s).

REFERENCE EXAMPLE 99

Under an argon atmosphere, to a suspension of sodium hydride (60%, 0.25g) in toluene (10 ml) was added dropwise a solution of ethyldiethylphosphonoacetate (1.22 ml) in toluene (10 ml) at 0° C. Afterstirring for 30 minutes at 0° C.,6-bromo-1-methyl-1,2,3,4-tetrahydroquinoline-8-carbaldehyde (1.30 g) intoluene (20 ml) was added dropwise thereto, and the mixture was heatedunder reflux for 2 hours. To the reaction system was added water, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, and dried over magnesium sulfate.After concentration under reduced pressure, the residue was separatedand purified by column chromatography (ethyl acetate:hexane 1:19→1:9) togive ethyl(2E)-3-(6-bromo-1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)acrylate (1.49g) as a pale yellow oily material.

H-NMR (200 MHz, CDCl₃) δ 1.33 (3H, t, J=7.1 Hz), 1.76-1.90 (2H, m),2.71-2.78 (5H, m), 3.10-3.15 (2H, m), 4.26 (2H, q, J=7.1 Hz), 6.32 (1H,d, J=16.1 Hz), 7.13 (1H, d, J=2.2 Hz), 7.41 (1H, d, J=2.2 Hz), 7.84 (1H,d, J=16.1 Hz).

IR (neat) 1711, 1632, 1451, 1470, 1416, 1310, 1265, 1233, 1175, 1040,912, 743 cm⁻¹

REFERENCE EXAMPLE 100

Under an argon atmosphere, a mixture of ethyl(2E)-3-(6-bromo-1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)acrylate (1.49g), 4-(2-butoxyethoxy)phenylboric acid (1.31 g) and potassium carbonate(1.27 g) in toluene (50 ml), ethanol (5 ml) and water (5 ml) was stirredfor 30 minutes at room temperature.Tetrakis(triphenylphosphine)palladium (0.26 g) was added to the reactionsystem, and the mixture was heated under reflux for 6 hours. Aftercooling to room temperature, the mixture was extracted with ethylacetate. The organic layer was washed with water and saturated brine,and dried over magnesium sulfate. After concentration under reducedpressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:19→1:7) to give ethyl(2E)-3-[6-[4-(2-butoxyethoxy)phenyl]-1-methyl-1,2,3,4-tetrahydroquinolin-8-yl]acrylate(1.56 g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.1 Hz), 1.26-1.48 (5H, m),1.50-1.70 (2H, m), 1.79-1.97 (2H, m), 2.76-2.89 (5H, m), 3.11-3.24 (2H,m), 3.55 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.0 Hz), 4.16 (2H, t, J=5.0Hz), 4.20 (2H, q, J=7.2 Hz), 6.42 (1H, d, J=16.2 Hz), 6.97 (2H, d, J=8.4Hz), 7.21-7.23 (1H, m), 7.46 (2H, d, J=8.4 Hz), 7.47-7.50 (1H, m), 7.99(1H, d, J=16.2 Hz).

IR (neat) 1709, 1630, 1609, 1516, 1454, 1275, 1248, 1177, 1125, 1040,910, 741 cm⁻¹

REFERENCE EXAMPLE 101

To a solution of ethyl(2E)-3-[6-[4-(2-butoxyethoxy)phenyl]-1-methyl-1,2,3,4-tetrahydroquinolin-8-yl]acrylate(1.56 g) in ethanol (20 ml) and THF (10 ml) was added a 1 N aqueoussodium hydroxide solution (8.0 ml) at room temperature. After stirringfor 20 hours at 65° C., 1 N hydrochloric acid (8.0 ml) was added theretoat 0° C., and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theprecipitated crystals were collected by filtration. The crystals werewashed with diisopropyl ether and hexane to give(2E)-3-[6-[4-(2-butoxyethoxy)phenyl]-1-methyl-1,2,3,4-tetrahydroquinolin-8-yl]acrylicacid (1.37 g) as yellow crystals.

m.p. 128-129° C.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.3 Hz), 1.29-1.48 (2H, m),1.55-1.68 (2H, m), 1.82-1.97 (2H, m), 2.82-2.86 (5H, m), 3.16-3.21 (2H,m), 3.56 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=4.9 Hz), 4.16 (2H, t, J=4.9Hz), 6.44 (1H, d, J=16.1 Hz), 6.98 (2H, d, J=8.8 Hz), 7.25 (1H, d, J=2.0Hz), 7.46 (2H, d, J=8.8 Hz), 7.52 (1H, d, J=2.0 Hz), 8.10 (1H, d, J=16.1Hz).

REFERENCE EXAMPLE 102

Under an argon atmosphere, to a suspension of sodium hydride (60%, 0.27g) in toluene (10 ml) was added dropwise a solution of ethyl2-(diethylphosphono)propionate (1.58 g) in toluene (10 ml) at 0° C.After stirring for 1 hour at 0° C.,6-bromo-1-methyl-1,2,3,4-tetrahydroquinoline-8-carbaldehyde (1.40 g) intoluene (20 ml) was added dropwise thereto, and the mixture was heatedunder reflux for 4 hours. To the reaction system was added water, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, and dried over magnesium sulfate.After concentration under reduced pressure, the residue was separatedand purified by column chromatography (ethyl acetate:hexane 1:19→1:15)to give ethyl(2E)-3-(6-bromo-1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-2-methylacrylate(1.677 g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 1.34 (3H, t, J=7.1 Hz), 1.75-1.89 (2H, m),2.06 (3H, d, J=1.4 Hz), 2.71-2.78 (5H, m), 3.10-3.15 (2H, m), 4.27 (2H,q, J=7.1 Hz), 7.10 (1H, d, J=2.2 Hz), 7.16 (1H, d, J=2.2 Hz), 7.59 (1H,s).

IR (neat) 1707, 1449, 1412, 1264, 1240, 1223, 1111, 1044, 912, 748 cm⁻¹

REFERENCE EXAMPLE 103

Under an argon atmosphere, a mixture of ethyl(2E)-3-(6-bromo-1-methyl-1,2,3,4-tetrahydroquinolin-8-yl)-2-methylacrylate(1.677 g), 4-(2-butoxyethoxy)phenylboric acid (1.42 g) and potassiumcarbonate (1.37 g) in toluene (50 ml), ethanol (5 ml) and water (5 ml)was stirred for 30 minutes at room temperature.Tetrakis(triphenylphosphine)palladium (0.17 g) was added to the reactionsystem, and the mixture was heated under reflux for 6 hours. Aftercooling to room temperature, the mixture was extracted with ethylacetate. The organic layer was washed with water and saturated brine,and dried over magnesium sulfate. After concentration under reducedpressure, the residue was separated and purified by columnchromatography (ethyl acetate:hexane 1:19→1:9) to give ethyl(2E)-3-[6-[4-(2-butoxyethoxy)phenyl]-1-methyl-1,2,3,4-tetrahydroquinolin-8-yl]-2-methylacrylate(1.55 g) as a yellow oily material.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.3 Hz), 1.27-1.47 (5H, m),1.51-1.68 (2H, m), 1.82-1.96 (2H, m), 2.13 (3H, d, J=1.2 Hz), 2.77 (3H,s), 2.80-2.87 (2H, m), 3.15-3.20 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80(2H, t, J=4.9 Hz), 4.15 (2H, t, J=4.9 Hz), 4.28 (2H, q, J=7.1 Hz), 6.96(2H, d, J=8.8 Hz), 7.19-7.29 (2H, m), 7.44 (2H, d, J=8.8 Hz), 7.74 (1H,s).

IR (neat) 1705, 1516, 1456, 1248, 1123, 912, 829 cm⁻¹

REFERENCE EXAMPLE 104

To a solution of ethyl(2E)-3-[6-[4-(2-butoxyethoxy)phenyl]-1-methyl-1,2,3,4-tetrahydroquinolin-8-yl]-2-methylacrylate(1.55 g) in ethanol (20 ml) and THF (10 ml) was added a 1 N aqueoussodium hydroxide solution (7.0 ml) at room temperature. After stirringfor 4 hours at 65° C., 1 N hydrochloric acid (7.0 ml) was added theretoat 0° C., and the mixture was extracted with ethyl acetate. The organiclayer was washed with water and saturated brine, and dried overmagnesium sulfate. After concentration under reduced pressure, theprecipitated crystals were collected by filtration. The crystals werewashed with diisopropyl ether and hexane to give(2E)-3-[6-[4-(2-butoxyethoxy)phenyl]-1-methyl-1,2,3,4-tetrahydroquinolin-8-yl]-2-methylacrylicacid (1.27 g) as yellow crystals.

m.p. 133-134° C.

¹H-NMR (200 MHz, CDCl₃) δ 0.93 (3H, t, J=7.4 Hz), 1.28-1.47 (2H, m),1.54-1.68 (2H, m), 1.82-1.97 (2H, m), 2.17 (3H, d, J=1.6 Hz), 2.79-2.87(5H, m), 3.16-3.22 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.0Hz), 4.16 (2H, t, J=5.0 Hz), 6.97 (2H, d, J=8.8 Hz), 7.21 (1H, d, J=2.2Hz), 7.30 (1H, d, J=2.2 Hz), 7.44 (2H, d, J=8.8 Hz), 7.90 (1H, s).

REFERENCE EXAMPLE 105

5-Bromo-2-fluorobenzaldehyde (2.5 g), N-(2-methoxyethyl)methylamine(1.43 g), sodium carbonate (3.91 g) were added to dimethyl sulfoxide (40ml) and water (20 ml), and the mixture was stirred for 6 hours at 90° C.under a nitrogen atmosphere. After returning to room temperature, waterwas added thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over magnesiumsulfate. The solvent was distilled off under reduced pressure, and thenthe resulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=6:1→hexane:ethyl acetate=1:1) to give5-bromo-2-[(2-methoxyethyl)(methyl)amino]benzaldehyde (2.47 g) as ayellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 2.93 (3H, s), 3.29-3.33 (5H, m), 3.56 (2H, t,J=5.4 Hz), 7.02 (1H, d, J=9.0 Hz), 7.54 (1H, dd, J=9.0, 2.4 Hz), 7.86(1H, d, J=2.4 Hz), 10.21 (1H, s).

REFERENCE EXAMPLE 106

To a suspension of sodium hydride (194 mg) in toluene (10 ml) was addeddropwise a solution of ethyl diethylphosphonoacetate (987 mg) in toluene(10 ml) at 0° C. under a nitrogen atmosphere, and then the mixture wasstirred as such for 1 hour. Next, a solution of5-bromo-2-[(2-methoxyethyl)(methyl)amino]benzaldehyde (1.0 g) in toluene(10 ml) was added dropwise thereto at 0° C. under a nitrogen atmosphere,and then the resulting mixture was refluxed for 3 hours. After removingfrom the oil bath, water was added thereto and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=6:1) to give ethyl(2E)-3-[5-bromo-2-[(2-methoxyethyl)(methyl)amino]phenyl]acrylate (1.03g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 1.34 (3H, t, J=7.2 Hz), 2.80 (3H, s), 3.12(2H, t, J=6.0 Hz), 3.32 (3H, s), 3.54 (2H, t, J=6.0 Hz), 4.26 (2H, q,J=7.2 Hz), 6.35 (1H, d, J=16.2 Hz), 6.96 (1H, d, J=8.4 Hz), 7.39 (1H,dd, J=8.4, 2.4 Hz), 7.59 (1H, d, J=2.4 Hz), 7.94 (1H, d, J=16.2 Hz).

REFERENCE EXAMPLE 107

A suspension of ethyl(2E)-3-[5-bromo-2-[(2-methoxyethyl)(methyl)amino]phenyl]acrylate (900mg), 4-(2-butoxyethoxy)phenylboric acid (814 mg) and potassium carbonate(945 mg) in toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) wasstirred for 1 hour under an argon atmosphere. Then,tetrakis(triphenylphosphine)palladium (152 mg) was added thereto, andthe resulting mixture was refluxed for 6 hours. After returning to roomtemperature, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=19:1→hexane:ethylacetate=5:1) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-[(2-methoxyethyl)(methyl)amino]-1,1′-biphenyl-3-yl]acrylate(1.19 g) as a yellow oily material. Ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-[(2-methoxyethyl)(methyl)amino]-1,1′-biphenyl-3-yl]acrylate(980 mg) was dissolved in THF (25 ml) and methanol (25 ml). Then, a 1 Naqueous sodium hydroxide solution (8.6 ml) was added thereto, and themixture was stirred for 3 hours at 90° C. After adding water at 0° C.,the resulting mixture was neutralized with 1 N hydrochloric acid andextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waswashed with hexane to give(2E)-3-[4′-(2-butoxyethoxy)-4-[(2-methoxyethyl)(methyl)amino]-1,1′-biphenyl-3-yl]acrylicacid (717 mg) as yellow crystals.

m.p. 86.4-87.4° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J=7.5 Hz), 1.34-1.46 (2H, m),1.56-1.66 (2H, m), 2.87 (3H, s), 3.19 (2H, t, J=6.6 Hz), 3.37 (3H, s),3.56 (2H, t, J=6.6 Hz), 3.61 (2H, t, J=6.0 Hz), 3.82 (2H, t, J=5.1 Hz),4.17 (2H, t, J=5.1 Hz), 6.47 (1H, d, J=16.2 Hz), 7.01 (2H, d, J=7.8 Hz),7.18 (1H, d, J=8.7 Hz), 7.49 (2H, d, J=7.8 Hz), 7.54 (1H, dd, J=8.7, 2.1Hz), 7.71 (1H, d, J=2.1 Hz), 8.23 (1H, d, J=16.2 Hz).

Elementary analysis C₂₅H₃₃NO₅, Calcd. C, 70.23; H, 7.78; N, 3.28. FoundC, 70.08; H, 7.84; N, 3.26.

REFERENCE EXAMPLE 108

1-Methylpyrazole-4-carboxyaldehyde (1.2 g), methylamine hydrochloride(736 mg) and triethylamine (3.04 ml) were dissolved in methanol (15 ml),and then palladium carbon (10%, 0.2 g) was added thereto, and themixture was stirred overnight under a hydrogen atmosphere. Theinsolubles were removed by filtration, and then the solvent wasdistilled off under reduced pressure. To the resulting residue wereadded DMSO (20 ml), water (15 ml) and sodium carbonate (3.47 g), andthen a solution of 5-bromo-2-fluorobenzaldehyde (2.21 g) in DMSO (10 ml)was added dropwise thereto at 115° C. under a nitrogen atmosphere. Afterstirring as such for 5 hours at 115° C., the reaction mixture wasreturned to room temperature. Water was added thereto and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue wasseparated and purified by silica gel column chromatography (hexane:ethylacetate=3:1→hexane:ethyl acetate=1:1), which was recrystallized fromhexane-ethyl acetate to give5-bromo-2-[methyl[(1-methyl-1H-pyrazol-4-yl)methyl]amino]benzaldehyde(784 mg) as brown crystals.

m.p. 80.0-81.0° C.

¹H-NMR (300 MHz, CDCl₃) δ 2.78 (3H, s), 3.86 (3H, s), 4.14 (2H, s), 6.92(1H, d, J=9.0 Hz), 7.18 (1H, s), 7.30 (1H, s), 7.54 (1H, dd, J=9.0, 2.7Hz), 7.89 (1H, d, J=2.7 Hz), 10.25 (1H, s).

Elementary analysis C₁₃H₁₄N₃OBr, Calcd. C, 50.67; H, 4.58; N, 13.64.Found C, 50.68; H, 4.48; N, 13.44.

REFERENCE EXAMPLE 109

To a suspension of sodium hydride (72 mg) in toluene (10 ml) was addeddropwise a solution of ethyl diethylphosphonoacetate (365 mg) in toluene(10 ml) at 0° C. under a nitrogen atmosphere, and then the mixture wasstirred as such for 1 hour. Next, a solution of5-bromo-2-[methyl[(1-methyl-1H-pyrazol-4-yl)methyl]amino]benzaldehyde(420 mg) in toluene (10 ml) was added dropwise thereto at 0° C. under anitrogen atmosphere, and then the resulting mixture was refluxed for 3hours. After removing from the oil bath, water was added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waspurified by silica gel column chromatography (hexane:ethylacetate=7:3→ethyl acetate) and recrystallized from hexane-ethyl acetateto give ethyl(2E)-3-[5-bromo-2-[methyl[(1-methyl-1H-pyrazol-4-yl)methyl]amino]phenyl]acrylate(310 mg) as yellow crystals.

m.p. 67.0-68.0° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.35 (3H, t, J=7.5 Hz), 2.65 (3H, s), 3.87(5H, s), 4.27 (2H, q, J=7.5 Hz), 6.40 (1H, d, J=16.2 Hz), 6.86 (1H, d,J=8.7 Hz), 7.31 (1H, s), 7.34 (1H, s), 7.38 (1H, dd, J=8.7, 2.4 Hz),7.64 (1H, d, J=2.4 Hz), 8.06 (1H, d, J=16.2 Hz).

Elementary analysis C₁₇H₂₀N₃O₂Br, Calcd. C, 53.98; H, 5.33; N, 11.11.Found C, 53.94; H, 5.25; N, 10.96.

REFERENCE EXAMPLE 110

A suspension of ethyl(2E)-3-[5-bromo-2-[methyl[(1-methyl-1H-pyrazol-4-yl)methyl]amino]phenyl]acrylate(450 mg), 4-(2-butoxyethoxy)phenylboric acid (369 mg) and potassiumcarbonate (427 mg) in toluene (15 ml), ethanol (1.5 ml) and water (1.5ml) was stirred for 1 hour under an argon atmosphere. Then,tetrakis(triphenylphosphine)palladium (69 mg) was added thereto, and theresulting mixture was refluxed for 6 hours. After returning to roomtemperature, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=3:1→ethyl acetate) togive ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-[methyl[(1-methyl-1H-pyrazol-4-yl)methyl]amino]-1,1′-biphenyl-3-yl]acrylate(522 mg) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J=7.2 Hz), 1.34-1.46 (5H, m),1.55-1.67 (2H, m), 2.70 (3H, s), 3.56 (2H, t, J=6.6 Hz), 3.82 (2H, t,J=4.8 Hz), 3.89 (3H, s), 3.93 (2H, s), 4.17 (2H, t, J=4.8 Hz), 4.29 (2H,q, J=7.2 Hz), 6.51 (1H, d, J=13.2 Hz), 7.00 (2H, d, J=8.7 Hz), 7.07 (1H,d, J=8.4 Hz), 7.38 (1H, s), 7.40 (1H, s), 7.48-7.53 (3H, m), 7.73 (1H,d, J=2.1 Hz), 8.23 (1H, d, J=13.2 Hz).

REFERENCE EXAMPLE 111

Ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-[methyl[(1-methyl-1H-pyrazol-4-yl)methyl]amino]-1,1′-biphenyl-3-yl]acrylate(495 mg) was dissolved in THF (12 ml) and methanol (12 ml). Then, a 1 Naqueous sodium hydroxide solution (4 ml) was added thereto, and themixture was stirred for 5 hours at 90° C. After adding water at 0° C.,the resulting mixture was neutralized with 1 N hydrochloric acid andextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waswashed with hexane-diisopropyl ether to give(2E)-3-[4′-(2-butoxyethoxy)-4-[methyl[(1-methyl-1H-pyrazol-4-yl)methyl]amino]-1,1′-biphenyl-3-yl]acrylicacid (425 mg) as yellow crystals.

m.p. 125.0-127.0° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J=7.5 Hz), 1.36-1.44 (2H, m),1.50-1.70 (2H, m), 2.72 (3H, s), 3.56 (2H, t, J=6.6 Hz), 3.82 (2H, t,J=4.5 Hz), 3.92 (5H, s), 4.17 (2H, t, J=4.5 Hz), 6.52 (1H, d, J=15.9Hz), 7.01 (2H, d, J=8.7 Hz), 7.10 (1H, d, J=8.1 Hz), 7.37 (1H, s),7.49-7.55 (4H, m), 7.76 (1H, d, J=2.1 Hz), 8.34 (1H, d, J=15.9 Hz).

Elementary analysis C₂₈H₃₃N₃O₄.0.5H₂O, Calcd. C, 69.40; H, 7.07; N,8.67. Found C, 69.69; H, 7.24; N, 8.87.

REFERENCE EXAMPLE 112

To a suspension of sodium hydride (52 mg) in toluene (10 ml) was addeddropwise a solution of triethyl 2-phosphonopropionate (278 mg) intoluene (10 ml) at 0° C. under a nitrogen atmosphere, and then themixture was stirred as such for 1 hour. Next, a solution of5-bromo-2-[methyl[(1-methyl-1H-pyrazol-4-yl)methyl]amino]benzaldehyde(300 mg) in toluene (10 ml) was added dropwise thereto at 0° C. under anitrogen atmosphere, and then the resulting mixture was refluxed for 3hours. After removing from the oil bath, water was added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waspurified by basic silica gel column chromatography (ethyl acetate) togive ethyl(2E)-3-[5-bromo-2-[methyl[(1-methyl-1H-pyrazol-4-yl)methyl]amino]phenyl]-2-methylacrylate(381 mg) as a brown oily material.

¹H-NMR (300 MHz, CDCl₃) δ 1.36 (3H, t, J=6.9 Hz), 2.10 (3H, d, J=1.5Hz), 2.62 (3H, s), 3.82 (2H, s), 3.86 (3H, s), 4.28 (2H, q, J=6.9 Hz),6.84 (1H, d, J=8.7 Hz), 7.25-7.40 (4H, m), 7.79 (1H, s).

REFERENCE EXAMPLE 113

A suspension of ethyl(2E)-3-[5-bromo-2-[methyl[(1-methyl-1H-pyrazol-4-yl)methyl]amino]phenyl]-2-methylacrylate(360 mg), 4-(2-butoxyethoxy)phenylboric acid (283 mg) and potassiumcarbonate (330 mg) in toluene (10 ml), ethanol (1 ml) and water (1 ml)was stirred for 1 hour under an argon atmosphere. Then,tetrakis(triphenylphosphine)palladium (53 mg) was added thereto, and theresulting mixture was refluxed for 6 hours. After returning to roomtemperature, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=2:1→hexane:ethyl acetate1:4) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-[methyl[(1-methyl-1H-pyrazol-4-yl)methyl]amino]-1,1′-biphenyl-3-yl]-2-methylacrylate(344 mg) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.33-1.46 (5H, m),1.50-1.66 (2H, m), 2.17 (3H, d, J=1.2 Hz), 2.68 (3H, s), 3.55 (2H, t,J=6.9 Hz), 3.81 (2H, t, J=4.8 Hz), 3.85-3.87 (5H, m), 4.16 (2H, t, J=4.8Hz), 4.30 (2H, q, J=7.2 Hz), 6.99 (2H, d, J=9.0 Hz), 7.05 (1H, d, J=8.7Hz), 7.32 (1H, s), 7.40 (1H, s), 7.45-7.49 (4H, m), 7.96 (1H, s).

REFERENCE EXAMPLE 114

Ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-[methyl[(1-methyl-1H-pyrazol-4-yl)methyl]amino]-1,1′-biphenyl-3-yl]-2-methylacrylate(330 mg) was dissolved in THF (8 ml) and methanol (8 ml). Then, a 1 Naqueous sodium hydroxide solution (2.6 ml) was added thereto, and themixture was stirred for 5 hours at 90° C. After adding water at 0° C.,the resulting mixture was neutralized with 1 N hydrochloric acid andextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waswashed with hexane to give(2E)-3-[4′-(2-butoxyethoxy)-4-[methyl[(1-methyl-1H-pyrazol-4-yl)methyl]amino]-1,1′-biphenyl-3-yl]-2-methylacrylicacid (260 mg) as yellow crystals.

m.p. 139.5-140.5° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J=7.5 Hz), 1.34-1.46 (2H, m),1.57-1.66 (2H, m), 2.21 (3H, d, J=1.5 Hz), 2.69 (3H, s), 3.56 (2H, t,J=6.6 Hz), 3.82 (2H, t, J=4.8 Hz), 3.85 (2H, s), 3.94 (3H, s), 4.17 (2H,t, J=4.8 Hz), 7.01 (2H, d, J=9.0 Hz), 7.10 (1H, d, J=7.8 Hz), 7.34 (1H,s), 7.46-7.56 (4H, m), 7.65 (1H, s), 8.12 (1H, s).

Elementary analysis C₂₈H₃₅N₃O₄.0.25H₂O, Calcd. C, 69.76; H, 7.42; N,8.72. Found C, 69.98; H, 7.37; N, 8.42.

REFERENCE EXAMPLE 115

To a solution of 4-bromofluorobenzene (15.0 g) in dry tetrahydrofuran(150 ml) was added dropwise LDA (2.0 M, 55.7 ml) at −78° C. under anargon atmosphere. After stirring as such for 2 hours, a solution ofN-methoxy-N-methylacetamide (10.6 g) in dry tetrahydrofuran (20 ml) wasadded dropwise thereto. The reaction mixture was returned to roomtemperature and stirred for 2 hours, which was acidified with 1 Nhydrochloric acid and extracted with ether. The organic layer was washedwith saturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue wasseparated and purified by silica gel column chromatography (hexane:ethylacetate=50:1→hexane:ethyl acetate=25:1) to give1-(5-bromo-2-fluorophenyl)ethanone (13.1 g) as a colorless oilymaterial.

¹H-NMR (300 MHz, CDCl₃) δ 2.64 (3H, d, J=5.1 Hz), 7.02-7.09 (1H, m),7.59-7.65 (1H, m), 7.98-8.01 (1H, m).

REFERENCE EXAMPLE 116

To a solution of pyrrolidine (3.85 ml) and potassium carbonate (12.7 g)in DMF (60 ml) was added dropwise a solution of1-(5-bromo-2-fluorophenyl)ethanone (5.0 g) in DMF (20 ml) at 75° C.under a nitrogen atmosphere, and the mixture was heated while stirringfor 6 hours as such. After returning to room temperature, water wasadded thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over magnesiumsulfate. The solvent was distilled off under reduced pressure, and thenthe resulting residue was separated and purified by silica gel columnchromatography (hexane:ethyl acetate=19:1) to give1-(5-bromo-2-pyrrolidin-1-ylphenyl)ethanone (2.28 g) as a brown oilymaterial.

¹H-NMR (300 MHz, CDCl₃) δ 1.93-1.98 (4H, m), 2.57 (3H, s), 3.07-3.11(4H, m), 6.70 (1H, d, J=9.0 Hz), 7.37 (1H, dd, J=9.0, 2.4 Hz), 7.58 (1H,d, J=2.4 Hz).

REFERENCE EXAMPLE 117

A suspension of 1-(5-bromo-2-pyrrolidin-1-ylphenyl)ethanone (750 mg),4-(2-butoxyethoxy)phenylboric acid (867 mg) and potassium carbonate (1.0g) in toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) was stirredfor 1 hour under an argon atmosphere. Then,tetrakis(triphenylphosphine)palladium (162 mg) was added thereto, andthe resulting mixture was refluxed for 6 hours. After returning to roomtemperature, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=19:1→hexane:ethylacetate=6:1). The resulting solids were washed with hexane to give1-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]ethanone(495 mg) as yellow crystals.

m.p. 87.0-88.0° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.36-1.46 (2H, m),1.55-1.66 (2H, m), 1.94-1.99 (4H, m), 2.64 (3H, s), 3.15-3.20 (4H, m),3.55 (2H, t, J=6.9 Hz), 3.81 (2H, t, J=4.8 Hz), 4.16 (2H, t, J=4.8 Hz),6.88 (1H, d, J=9.0 Hz), 6.98 (2H, d, J=9.0 Hz), 7.46 (2H, d, J=9.0 Hz),7.53 (1H, dd, J=9.0, 2.1 Hz), 7.66 (1H, d, J=2.1 Hz).

Elementary analysis C₂₄H₃₁NO₃, Calcd. C, 75.56; H, 8.19; N, 3.67. FoundC, 75.52; H, 8.19; N, 3.41.

REFERENCE EXAMPLE 118

To a suspension of sodium hydride (296 mg) in toluene (10 ml) was addeddropwise a solution of ethyl diethylphosphonoacetate (1.24 ml) intoluene (20 ml) at 0° C. under a nitrogen atmosphere, and the mixturewas stirred as such for 1 hour. Next, a solution of1-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]ethanone(470 mg) in toluene (10 ml) was added dropwise thereto at 0° C. under anitrogen atmosphere, and then the resulting mixture was refluxed for 3hours. After removing from the oil bath, water was added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waspurified by basic silica gel column chromatography(ethyl acetate). Theresulting solids were washed with hexane to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]but-2-enoate(250 mg) as yellow crystals.

m.p. 81.0-82.0° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.5 Hz), 1.24-1.43 (5H, m),1.50-1.65 (2H, m), 1.85-1.95 (4H, m), 2.50 (3H, s), 3.15-3.25 (4H, m),3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.8 Hz), 4.11-4.25 (4H, m), 5.98(1H, s), 6.85 (1H, d, J=9.0 Hz), 6.96 (2H, d, J=8.4 Hz), 7.25 (1H, d,J=2.7 Hz), 7.40 (1H, dd, J=9.0, 2.7 Hz), 7.46 (2H, d, J=8.4 Hz).

Elementary analysis C₂₈H₃₇NO₄.0.5H₂O, Calcd. C, 73.01; H, 8.32; N, 3.04.Found C, 73.06; H, 8.15; N, 2.87.

REFERENCE EXAMPLE 119

Ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]but-2-enoate(260 mg) was dissolved in THF (7 ml) and methanol (7 ml). Then, a 1 Naqueous sodium hydroxide solution (2.3 ml) was added thereto, and themixture was stirred for 3 hours at 90° C. After adding water at 0° C.,the resulting mixture was neutralized with 1 N hydrochloric acid andextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waswashed with hexane to give(2E)-3-[4′-(2-butoxyethoxy)-4-pyrrolidin-1-yl-1,1′-biphenyl-3-yl]but-2-enoicacid (158 mg) as yellow crystals.

m.p. 127.5-128.5° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.35-1.43 (2H, m),1.56-1.63 (2H, m), 1.90-1.94 (4H, m), 2.52 (3H, d, J=1.2 Hz), 3.19-3.23(4H, m), 3.54 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.5 Hz), 4.15 (2H, t,J=4.5 Hz), 6.01 (1H, d, J=1.5 Hz), 6.86 (1H, d, J=8.7 Hz), 6.96 (2H, d,J=8.4 Hz), 7.26 (1H, d, J=2.4 Hz), 7.40 (1H, dd, J=8.7, 2.4 Hz), 7.45(2H, d, J=8.4 Hz).

Elementary analysis C₂₆H₃₃NO₄.0.5H₂O, Calcd. C, 72.19; H, 7.92; N, 3.24.Found C, 72.20; H, 7.74; N, 2.97.

REFERENCE EXAMPLE 120

A suspension of 5-bromo-2-fluorobenzaldehyde (2.0 g), 3-pyrroline (0.98ml) and potassium carbonate (1.77 g) in DMF (30 ml) was heated for 5hours at 75° C. under a nitrogen atmosphere. After returning to roomtemperature, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was separated andpurified by silica gel column chromatography (hexane:ethylacetate=19:1→hexane ethyl acetate=6:1). The resulting solids were washedwith hexane to give 5-bromo-2-(2,5-dihydro-1H-pyrrol-1-yl)benzaldehyde(592 mg) as yellow crystals.

m.p. 88.2-89.2° C.

¹H-NMR (300 MHz, CDCl₃) δ 4.21 (4H, s), 5.95 (2H, s), 6.68 (1H, d, J=9.0Hz), 7.46 (1H, dd, J=9.0, 2.4 Hz), 7.82 (1H, d, J=2.4 Hz), 10.08 (1H,s).

Elementary analysis C₁₁H₁₀NOBr, Calcd. C, 52.41; H, 4.00; N, 5.56. FoundC, 52.24; H, 3.94; N, 5.33.

REFERENCE EXAMPLE 121

A suspension of 5-bromo-2-(2,5-dihydro-1H-pyrrol-1-yl)benzaldehyde (550mg), 4-(2-butoxyethoxy)phenylboric acid (676 mg) and potassium carbonate(784 mg) in toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) wasstirred for 1 hour under an argon atmosphere. Then,tetrakis(triphenylphosphine)palladium (126 mg) was added thereto, andthe resulting mixture was refluxed for 5 hours. After returning to roomtemperature, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=19:1→hexane:ethylacetate=5:1) and recrystallized from hexane-ethyl acetate to give4′-(2-butoxyethoxy)-4-(2,5-dihydro-1H-pyrrol-1-yl)-1,1′-biphenyl-3-carbaldehyde(431 mg) as yellow crystals.

m.p. 79.0-81.0° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=8.7 Hz), 1.34-1.45 (2H, m),1.48-1.68 (2H, m), 3.55 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=4.8 Hz), 4.16(2H, t, J=4.8 Hz), 4.28 (4H, s), 5.96 (2H, s), 6.87 (1H, d, J=8.7 Hz),6.99 (2H, d, J=9.0 Hz), 7.49 (2H, d, J=9.0 Hz), 7.64 (1H, dd, J=8.7, 2.4Hz), 7.92 (1H, d, J=2.4 Hz), 10.21 (1H, s).

Elementary analysis C₂₃H₂₇NO₃, Calcd. C, 75.59; H, 7.45; N, 3.83. FoundC, 75.48; H, 7.46; N, 3.66.

REFERENCE EXAMPLE 122

To a suspension of sodium hydride (61 mg) in toluene (10 ml) was addeddropwise a solution of triethyl 2-phosphonopropionate (0.3 ml) intoluene (10 ml) at 0° C. under a nitrogen atmosphere, and the mixturewas stirred as such for 1 hour. Next, a solution of4′-(2-butoxyethoxy)-4-(2,5-dihydro-1H-pyrrol-1-yl)-1,1′-biphenyl-3-carbaldehyde(390 mg) in toluene (10 ml) was added dropwise thereto at 0° C. under anitrogen atmosphere, and then the resulting mixture was refluxed for 3hours. After removing from the oil bath, water was added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waspurified by basic silica gel column chromatography (hexane:ethyl acetate10:1→hexane:ethyl acetate=4:1) to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(2,5-dihydro-1H-pyrrol-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylate(389 mg) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.5 Hz), 1.30-1.70 (7H, m),2.01 (3H, s), 3.52-3.58 (2H, m), 3.79 (2H, t, J=4.8 Hz), 4.13-4.31 (8H,m), 5.87 (2H, t, J=4.2 Hz), 6.81 (1H, d, J=9.0 Hz), 6.95 (2H, d, J=9.0Hz), 7.38-7.46 (4H, m), 7.91 (1H, s).

REFERENCE EXAMPLE 123

Ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(2,5-dihydro-1H-pyrrol-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylate(360 mg) was dissolved in THF (10 ml) and methanol (10 ml). Then, a 1 Naqueous sodium hydroxide solution (3.2 ml) was added thereto, and themixture was stirred for 3 hours at 90° C. After adding water at 0° C.,the resulting mixture was neutralized with 1 N hydrochloric acid andextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waswashed with hexane to give(2E)-3-[4′-(2-butoxyethoxy)-4-(2,5-dihydro-1H-pyrrol-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylicacid (265 mg) as yellow crystals.

m.p. 138.5-139.5° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.33-1.45 (2H, m),1.56-1.65 (2H, m), 2.04 (3H, s), 3.55 (2H, t, J=6.9 Hz), 3.80 (2H, t,J=5.1 Hz), 4.15 (2H, t, J=5.1 Hz), 4.20 (4H, s), 5.88 (2H, s), 6.82 (1H,d, J=9.0 Hz), 6.96 (2H, d, J=8.7 Hz), 7.28 (1H, d, J=2.1 Hz), 7.40-7.45(3H, m), 8.06 (1H, s).

Elementary analysis C₂₆H₃₁NO₄, Calcd. C, 74.08; H, 7.41; N, 3.32. FoundC, 74.21; H, 7.29; N, 3.17.

REFERENCE EXAMPLE 124

To a solution of 5-bromo-2-(3-hydroxypyrrolidin-1-yl)benzaldehyde (6.4g) and 3,4-dihydro-2H-pyran (4.33 ml) in dichloromethane (70 ml) wasadded pyridinium p-toluenesulfonate (1.19 g), and the mixture wasstirred overnight under a nitrogen atmosphere. Water was added theretoand the mixture was extracted with ethyl acetate. The organic layer waswashed with an aqueous saturated sodium hydrogen carbonate solution andsaturated brine, and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure to give5-bromo-2-[3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidin-1-yl]benzaldehyde(8.15 g) as a brown oily material. To a suspension of sodium hydride(1.41 g) in toluene (50 ml) was added dropwise a solution of triethyl2-phosphonopropionate (6.88 ml) in toluene (50 ml) at 0° C. under anitrogen atmosphere, and the mixture was stirred as such for 1 hour.Next, a solution of5-bromo-2-[3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidin-1-yl]benzaldehyde(8.5 g) in toluene (50 ml) was added dropwise thereto at 0° C. under anitrogen atmosphere, and then the resulting mixture was refluxed for 3hours. After removing from the oil bath, water was added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and then dried over magnesium sulfate. The solventwas distilled off under reduced pressure, and then the resulting residuewas purified by basic silica gel column chromatography (hexane:ethylacetate 6:1) to give ethyl(2E)-3-[5-bromo-2-[3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidin-1-yl]phenyl]-2-methylacrylate(9.69 g) as a yellow oily material. To a solution of ethyl(2E)-3-[5-bromo-2-[3-(tetrahydro-2H-pyran-2-yloxy)pyrrolidin-1-yl]phenyl]-2-methylacrylate(9.5 g) in methanol (270 ml) was added 1 N hydrochloric acid (86.8 ml),and the mixture was stirred for 2 hours. After distilling off thesolvent under reduced pressure, water was added thereto and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waspurified by silica gel column chromatography (hexane:ethylacetate=1:1→ethyl acetate) to give ethyl(2E)-3-[5-bromo-2-(3-hydroxypyrrolidin-1-yl)phenyl]-2-methylacrylate(7.38 g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 1.34 (3H, t, J=7.2 Hz), 1.69 (1H, d, J=5.1Hz), 1.90-2.05 (4H, m), 2.07-2.25 (1H, m), 3.08-3.18 (2H, m), 3.41-3.53(2H, m), 4.26 (2H, q, J=7.2 Hz), 4.43-4.53 (1H, m), 6.69 (1H, d, J=8.7Hz), 7.20-7.35 (2H, m), 7.66 (1H, s).

REFERENCE EXAMPLE 125

To a solution of oxalyl chloride (1.2 ml) in dichloromethane (20 ml) wasadded dropwise a solution of DMSO (2.1 ml) in dichloromethane (20 ml) at−78° C. under an argon atmosphere. After stirring as such for 15minutes, a solution of ethyl(2E)-3-[5-bromo-2-(3-hydroxypyrrolidin-1-yl)phenyl]-2-methylacrylate(3.5 g) in dichloromethane (20 ml) was added dropwise thereto. Afterstirring as such for 15 minutes, triethylamine (8.26 ml) was addeddropwise thereto. The reaction mixture was stirred as such for 2 hours,and then returned to room temperature. Water was added thereto andextracted with ethyl acetate. The organic layer was washed withsaturated brine. The solvent was distilled off under reduced pressure,and then the resulting residue was purified by silica gel columnchromatography (hexane:ethyl acetate=1:1) to give ethyl(2E)-3-[5-bromo-2-(3-oxopyrrolidin-1-yl)phenyl]-2-methylacrylate (2.67g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 1.34 (3H, t, J=6.9 Hz), 2.04 (3H, s), 2.62(2H, t, J=6.9 Hz), 3.47-3.52 (4H, m), 4.27 (2H, q, J=6.9 Hz), 6.81 (1H,d, J=8.7 Hz), 7.33 (1H, d, J=2.4 Hz), 7.37 (1H, dd, J=8.7, 2.4 Hz), 7.59(1H, s).

REFERENCE EXAMPLE 126

A suspension of ethyl(2E)-3-[5-bromo-2-(3-oxopyrrolidin-1-yl)phenyl]-2-methylacrylate (2.6g), 4-(2-butoxyethoxy)phenylboric acid (2.29 g) and potassium carbonate(2.65 g) in toluene (50 ml), ethanol (5 ml) and water (5 ml) was stirredfor 1 hour under an argon atmosphere. Then,tetrakis(triphenylphosphine)palladium (597 mg) was added thereto, andthe resulting mixture was refluxed for 5 hours. After returning to roomtemperature, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=19:1→hexane:ethylacetate=5:1). The resulting solids were washed with hexane to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(3-oxopyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylate(1.51 g) as yellow crystals.

m.p. 98.5-99.0° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.32-1.46 (5H, m),1.50-1.66 (2H, m), 2.11 (3H, d, J=1.5 Hz), 2.65 (2H, t, J=7.2 Hz),3.53-3.58 (6H, m), 3.81 (2H, t, J=4.8 Hz), 4.16 (2H, t, J=4.8 Hz), 4.28(2H, q, J=7.2 Hz), 6.98-7.02 (3H, m), 7.42-7.51 (4H, m), 7.55 (1H, s).

Elementary analysis C₂₈H₃₅NO₅, Calcd. C, 72.23; H, 7.58; N, 3.01. FoundC, 72.09; H, 7.37; N, 2.78.

REFERENCE EXAMPLE 127

To a solution of ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(3-oxopyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylate(1.25 g) and ethylene glycol (1.5 ml) in toluene (20 ml) was addedp-toluenesulfonic acid monohydrate (26 mg), and the mixture was refluxedovernight while dehydrating under a nitrogen atmosphere. The reactionmixture was returned to room temperature. Water and an aqueous saturatedsodium hydrogen carbonate solution were sequentially added thereto,which was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and the solvent was distilled off under reducedpressure. The resulting residue was subjected to a silica gel columnchromatography (hexane:ethyl acetate=4:1→hexane:ethyl acetate=1:1) togive ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-1,1′-biphenyl-3-yl]-2-methylacrylate(1.14 g) as a brown oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.33-1.45 (5H, m),1.50-1.65 (2H, m), 2.05 (3H, d, J=1.2 Hz), 2.15 (2H, t, J=6.9 Hz), 3.31(2H, s), 3.38 (2H, t, J=6.9 Hz), 3.55 (2H, t, J=6.9 Hz), 3.80 (2H, t,J=4.5 Hz), 3.95-3.99 (4H, m), 4.15 (2H, t, J=4.5 Hz), 4.28 (2H, q, J=6.9Hz), 6.86 (1H, d, J=8.1 Hz), 6.96 (2H, d, J=8.7 Hz), 7.34 (1H, d, J=2.4Hz), 7.39-7.46 (3H, m), 7.79 (1H, s).

REFERENCE EXAMPLE 128

Ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-1,1′-biphenyl-3-yl]-2-methylacrylate(1.1 g) was dissolved in THF (12 ml) and methanol (12 ml). Then, a 1 Naqueous sodium hydroxide solution (4.3 ml) was added thereto, and themixture was stirred overnight at 50° C. After adding water at 0° C., theresulting mixture was neutralized with 1 N hydrochloric acid andextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waswashed with hexane-diisopropyl ether to give(2E)-3-[4′-(2-butoxyethoxy)-4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-1,1′-biphenyl-3-yl]-2-methylacrylicacid (1.02 g) as yellow crystals.

m.p. 129.5-131.5° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.33-1.45 (2H, m),1.56-1.65 (2H, m), 2.08 (3H, d, J=1.5 Hz), 2.16 (2H, t, J=7.2 Hz), 3.33(2H, s), 3.40 (2H, t, J=6.9 Hz), 3.55 (2H, t, J=6.9 Hz), 3.80 (2H, t,J=4.8 Hz), 3.92-4.02 (4H, m), 4.15 (2H, t, J=4.8 Hz), 6.87 (1H, d, J=8.7Hz), 6.97 (2H, d, J=8.7 Hz), 7.36 (1H, d, J=2.1 Hz), 7.40-7.46 (3H, m),7.93 (1H, s).

Elementary analysis C₂₈H₃₅NO₆, Calcd. C, 69.83; H, 7.33; N, 2.91. FoundC, 69.67; H, 7.45; N, 2.65.

REFERENCE EXAMPLE 129

A suspension of 5-bromo-2-fluorobenzaldehyde (2.5 g),3-hydroxymethylpyrrolidine hydrochloride (3.39 g) and sodium carbonate(3.26 g) in DMSO (75 ml) and water (37.5 ml) was heated for 5 hours at75° C. under a nitrogen atmosphere. After returning to room temperature,water was added thereto and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover magnesium sulfate. The solvent was distilled off under reducedpressure, and then the resulting residue was separated and purified bysilica gel column chromatography (hexane:ethyl acetate=9:1→hexane:ethylacetate=1:4) to give5-bromo-2-[3-(hydroxymethyl)pyrrolidin-1-yl]benzaldehyde (2.9 g) as ayellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 1.77-1.89 (1H, m), 2.09-2.19 (1H, m),2.51-2.60 (1H, m), 3.26-3.50 (4H, m), 3.65-3.78 (2H, m), 6.73 (1H, d,J=9.0 Hz), 7.45 (1H, dd, J=9.0, 2.7 Hz), 7.79 (1H, d, J=2.7 Hz), 10.01(1H, s).

REFERENCE EXAMPLE 130

To a solution of5-bromo-2-[3-(hydroxymethyl)pyrrolidin-1-yl]benzaldehyde (2.85 g) inpyridine (11 ml) was added dropwise acetic anhydride (3.77 ml) at 0° C.under a nitrogen atmosphere. The mixture was returned to roomtemperature and stirred for 5 hours, and then the solvent was distilledoff under reduced pressure. To the resulting residue was added water at0° C. and further added sodium carbonate, which was neutralized andextracted with ethyl acetate. The organic layer was then washed withsaturated brine, and the solvent was distilled off under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane:ethyl acetate=3:1→hexane:ethyl acetate=2:1) togive [1-(4-bromo-2-formylphenyl)pyrrolidin-3-yl]methyl acetate (2.91 g)as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 1.80-1.90 (1H, m), 2.07 (3H, s), 2.10-2.33(1H, m), 2.61-2.71 (1H, m), 3.20-3.53 (4H, m), 4.02-4.22 (2H, m), 6.72(1H, d, J=9.3 Hz), 7.45 (1H, dd, J=9.3, 2.4 Hz), 7.79 (1H, d, J=2.4 Hz),10.01 (1H, s).

REFERENCE EXAMPLE 131

A solution of [1-(4-bromo-2-formylphenyl)pyrrolidin-3-yl]methyl acetate(2.47 g) and tert-butyl 2-(triphenylphosphoranylidene)propanoate (3.4 g)in toluene (100 ml) was refluxed overnight under a nitrogen atmosphere.After returning to room temperature, water was added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waspurified by basic silica gel column chromatography (hexane ethylacetate=4:1) to give tert-butyl(2E)-3-[2-[3-[(acetyloxy)methyl]pyrrolidin-1-yl]-5-bromophenyl]-2-methylacrylate(2.29 g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 1.53 (9H, s), 1.60-1.75 (1H, m), 1.95 (3H, d,J=1.5 Hz), 2.00-2.15 (4H, m), 2.53-2.63 (1H, m), 2.98-3.08 (1H, m),3.18-3.28 (3H, m), 3.95-4.16 (2H, m), 6.66 (1H, d, J=8.4 Hz), 7.20-7.33(2H, m), 7.52 (1H, s).

REFERENCE EXAMPLE 132

A suspension of tert-butyl(2E)-3-[2-[3-(acetoxymethyl)pyrrolidin-1-yl]-5-bromophenyl]-2-methylacrylate(1.2 g), 4-(2-butoxyethoxy)phenylboric acid (848 mg) and potassiumcarbonate (984 mg) in toluene (20 ml), ethanol (2 ml) and water (2 ml)was stirred for 1 hour under an argon atmosphere. Then,tetrakis(triphenylphosphine)palladium (158 mg) was added thereto, andthe resulting mixture was refluxed for 5 hours. After returning to roomtemperature, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=9:1→hexane:ethylacetate=3:1) to give tert-butyl(2E)-3-[4-[3-(acetoxymethyl)pyrrolidin-1-yl]-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]-2-methylacrylate(770 mg) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.30-1.80 (14H, m),1.95-2.15 (7H, m), 2.55-2.65 (1H, m), 3.07-3.13 (1H, m), 3.27-3.35 (3H,m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.5 Hz), 4.02-4.18 (4H, m),6.87 (1H, d, J=8.1 Hz), 6.97 (2H, d, J=9.0 Hz), 7.36-7.46 (4H, m), 7.69(1H, s).

REFERENCE EXAMPLE 133

tert-Butyl(2E)-3-[4-[3-(acetoxymethyl)pyrrolidin-1-yl]-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]-2-methylacrylate(750 mg) was dissolved in ethyl acetate (7.5 ml). Then, a 4 Nhydrochloric acid-ethyl acetate solution (11 ml) was added thereto, andthe mixture was stirred overnight under a nitrogen atmosphere. Water wasadded thereto at 0° C. and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overmagnesium sulfate. The solvent was distilled off under reduced pressure,and then the resulting residue was washed with hexane-diisopropyl etherto give(2E)-3-[4-[3-(acetoxymethyl)pyrrolidin-1-yl]-4′-(2-butoxyethoxy)-1,1′-biphenyl-3-yl]-2-methylacrylicacid (542 mg) as yellow crystals.

m.p. 109.5-111.0° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=6.9 Hz), 1.33-1.46 (2H, m),1.56-1.80 (3H, m), 2.00-2.20 (7H, m), 2.55-2.70 (1H, m), 3.10-3.15 (1H,m), 3.29-3.35 (3H, m), 3.55 (2H, t, J=6.6 Hz), 3.81 (2H, t, J=5.1 Hz),4.04-4.17 (4H, m), 6.90 (1H, d, J=8.7 Hz), 6.98 (2H, d, J=9.0 Hz), 7.38(1H, d, J=2.1 Hz), 7.41-7.47 (3H, m), 7.93 (1H, s).

Elementary analysis C₂₉H₃₇NO₆, Calcd. C, 70.28; H, 7.52; N, 2.83. FoundC, 70.03; H, 7.51; N, 2.72.

REFERENCE EXAMPLE 134

To a solution of methyl 1-benzylpyrrolidine-3-carboxylate in methanol(50 ml) and 1 N hydrochloric acid (16.9 ml) was added palladium carbon(10%, 1.8 g), and the mixture was stirred overnight under a hydrogenatmosphere. The insolubles were removed by filtration, and then thesolvent was distilled off under reduced pressure. Toluene was addedthereto, and then the solvent was again distilled off under reducedpressure to give methylpyrrolidine-3-carboxylate hydrochloride (2.71 g)as a yellow oily material.

¹H-NMR (300 MHz, DMSO-d₆) δ 1.95-2.25 (2H, m), 3.11-3.45 (5H, m), 3.66(3H, s), 9.23 (2H, br).

REFERENCE EXAMPLE 135

A suspension of 5-bromo-2-fluorobenzaldehyde (2.12 g),methylpyrrolidine-3-carboxylate hydrochloride (2.6 g) and potassiumcarbonate (3.63 g) in DMF (40 ml) was stirred overnight at 80° C. undera nitrogen atmosphere. After returning to room temperature, water wasadded thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over magnesiumsulfate. The solvent was distilled off under reduced pressure, and thenthe resulting residue was separated and purified by silica gel columnchromatography (hexane:ethyl acetate=16:1→hexane:ethyl acetate=4:1) togive methyl 1-(4-bromo-2-formylphenyl)pyrrolidine-3-carboxylate (816 mg)as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 2.26-2.33 (2H, m), 3.15-3.24 (1H, m),3.33-3.41 (1H, m), 3.47-3.58 (3H, m), 3.73 (3H, s), 6.75 (1H, d, J=9.0Hz), 7.46 (1H, dd, J=9.0, 2.4 Hz), 7.80 (1H, d, J=2.4 Hz), 10.01 (1H,s).

REFERENCE EXAMPLE 136

A solution of methyl 1-(4-bromo-2-formylphenyl)pyrrolidine-3-carboxylate(800 mg) and tert-butyl 2-(triphenylphosphoranylidene)propanoate (1.34g) in toluene (20 ml) was refluxed for 6 hours under a nitrogenatmosphere. After returning to room temperature, water was added theretoand the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over magnesium sulfate. Thesolvent was distilled off under reduced pressure, and then the resultingresidue was purified by silica gel column chromatography (hexane ethylacetate=10:1→hexane:ethyl acetate=1:4) to give methyl1-[4-bromo-2-[(1E)-3-tert-butoxy-2-methyl-3-oxoprop-1-enyl]phenyl]pyrrolidine-3-carboxylate(580 mg) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 1.53 (9H, s), 1.95 (3H, d, J=1.5 Hz),2.17-2.24 (2H, m), 3.10-3.15 (1H, m), 3.21-3.29 (2H, m), 3.41 (2H, d,J=7.5 Hz), 3.71 (3H, s), 6.69 (1H, d, J=8.7 Hz), 7.24-7.30 (2H, m), 7.53(1H, s).

REFERENCE EXAMPLE 137

A suspension of methyl1-[4-bromo-2-[(1E)-3-tert-butoxy-2-methyl-3-oxoprop-1-enyl]phenyl]pyrrolidine-3-carboxylate(550 mg), 4-(2-butoxyethoxy)phenylboric acid (402 mg) and potassiumcarbonate (466 mg) in toluene (15 ml), ethanol (1.5 ml) and water (1.5ml) was stirred for 1 hour under an argon atmosphere. Then,tetrakis(triphenylphosphine)palladium (75 mg) was added thereto, and theresulting mixture was refluxed for 5 hours. After returning to roomtemperature, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=18:1→hexane:ethylacetate=4:1) to give methyl1-[4′-(2-butoxyethoxy)-3-[(1E)-3-tert-butoxy-2-methyl-3-oxoprop-1-enyl]-1″1-biphenyl-4-yl]pyrrolidine-3-carboxylate(409 mg) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.33-1.45 (2H, m),1.51-1.65 (11H, m), 2.02 (3H, d, J=1.2 Hz), 2.19-2.26 (2H, m), 3.10-3.20(1H, m), 3.25-3.35 (2H, m), 3.48 (2H, d, J=7.5 Hz), 3.55 (2H, t, J=6.6Hz), 3.72 (3H, s), 3.80 (2H, t, J=4.5 Hz), 4.15 (2H, t, J=4.5 Hz), 6.89(1H, d, J=8.4 Hz), 6.97 (2H, d, J=8.7 Hz), 7.35-7.46 (4H, m), 7.68 (1H,s).

REFERENCE EXAMPLE 138

Methyl1-[4′-(2-butoxyethoxy)-3-[(1E)-3-tert-butoxy-2-methyl-3-oxoprop-1-enyl]-1′1-biphenyl-4-yl]pyrrolidine-3-carboxylate(400 mg) was dissolved in ethyl acetate (4 ml). Then, a 4 N hydrochloricacid-ethyl acetate solution (7 ml) was added thereto, and the mixturewas stirred for 4 hours under a nitrogen atmosphere. Water was addedthereto at 0° C. and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over magnesiumsulfate. After distilling off the solvent under reduced pressure, theresulting solids were washed with hexane to give(2E)-3-[4′-(2-butoxyethoxy)-4-[3-(methoxycarbonyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methylacrylicacid (273 mg) as yellow crystals.

m.p. 140.0-141.0° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.33-1.45 (2H, m),1.50-1.70 (2H, m), 2.10 (3H, d, J=1.2 Hz), 2.20-2.28 (2H, m), 3.10-3.25(1H, m), 3.28-3.40 (2H, m), 3.46-3.50 (2H, m), 3.55 (2H, t, J=6.6 Hz),3.73 (3H, s), 3.80 (2H, t, J=4.5 Hz), 4.16 (2H, t, J=4.5 Hz), 6.92 (1H,d, J=8.7 Hz), 6.98 (2H, d, J=8.7 Hz), 7.38-7.47 (4H, m), 7.91 (1H, s).

Elementary analysis C₂₈H₃₅NO₆, Calcd. C, 69.83; H, 7.33; N, 2.91. FoundC, 69.76; H, 7.45; N, 2.64.

REFERENCE EXAMPLE 139

To a solution of 1-benzyl-3,4dimethylpyrrolidine (9.0 g) in methanol(100 ml) and 1 N hydrochloric acid (48.9 ml) was added palladium carbon(10%, 4.5 g), and the mixture was stirred overnight under a hydrogenatmosphere. The insolubles were removed by filtration, and then thesolvent was distilled off under reduced pressure. Toluene was addedthereto, and then the solvent was again distilled off under reducedpressure. The resulting residue was washed with hexane to give3,4-dimethylpyrrolidine hydrochloride (5.93 g) as pale red crystals.

¹H-NMR (300 MHz, DMSO-d₆) δ 0.90 (6H, d, J=3.4 Hz), 2.22-2.31 (2H, m),2.73-2.82 (2H, m), 3.17-3.27 (2H, m), 9.32 (2H, br).

REFERENCE EXAMPLE 140

A suspension of 5-bromo-2-fluorobenzaldehyde (2.5 g),3,4-dimethylpyrrolidine hydrochloride (2.51 g) and sodium carbonate(3.59 g) in DMSO (50 ml) and water (25 ml) was stirred for 4 hours at80° C. under a nitrogen atmosphere. After returning to room temperature,water was added thereto and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover magnesium sulfate. The solvent was distilled off under reducedpressure, and then the resulting residue was separated and purified bysilica gel column chromatography (hexane:ethyl acetate=20:1→hexane:ethylacetate=6:1) to give 5-bromo-2-(3,4-dimethylpyrrolidin-1-yl)benzaldehyde(2.84 g) as a brown oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.99 (6H, d, J=6.9 Hz), 2.35-2.40 (2H, m),3.06-3.11 (2H, m), 3.44-3.49 (2H, m), 6.66 (1H, d, J=9.0 Hz), 7.39 (1H,dd, J=9.0, 2.7 Hz), 7.78 (1H, d, J=2.7 Hz), 10.00 (1H, s).

REFERENCE EXAMPLE 141

To a suspension of sodium hydride (550 mg) in toluene (30 ml) was addeddropwise a solution of triethyl 2-phosphonopropionate (2.66 ml) intoluene (20 ml) at 0° C. under a nitrogen atmosphere, and the mixturewas stirred as such for 1 hour. Next, a solution of5-bromo-2-(3,4-dimethylpyrrolidin-1-yl)benzaldehyde (2.7 g) in toluene(30 ml) was added dropwise thereto at 0° C. under a nitrogen atmosphere,and then the resulting mixture was refluxed for 3 hours. After removingfrom the oil bath, water was added thereto and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was purified by basicsilica gel column chromatography (hexane:ethyl acetate=19:1→hexane:ethylacetate=6:1) to give ethyl(2E)-3-[5-bromo-2-(3,4-dimethylpyrrolidin-1-yl)phenyl]-2-methylacrylate(3.48 g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.95 (6H, d, J=6.6 Hz), 1.34 (3H, t, J=6.9Hz), 1.95 (3H, d, J=1.5 Hz), 2.23-2.32 (2H, m), 2.90-2.95 (2H, m),3.30-3.35 (2H, m), 4.26 (2H, q, J=6.9 Hz), 6.61 (1H, d, J=8.7 Hz),7.19-7.27 (2H, m), 7.67 (1H, s).

REFERENCE EXAMPLE 142

A suspension of ethyl(2E)-3-[5-bromo-2-(3,4-dimethylpyrrolidin-1-yl)phenyl]-2-methylacrylate(3.35 g), 4-(2-butoxyethoxy)phenylboric acid (2.83 g) and potassiumcarbonate (3.29 g) in toluene (50 ml), ethanol (5 ml) and water (5 ml)was stirred for 1 hour under an argon atmosphere. Then,tetrakis(triphenylphosphine)palladium (530 mg) was added thereto, andthe resulting mixture was refluxed for 5 hours. After returning to roomtemperature, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=19:1→hexane:ethylacetate=6:1). The resulting residue was washed with hexane to give ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(3,4-dimethylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylate(1.77 g) as yellow crystals.

m.p. 67.0-69.0° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.88-0.98 (9H, m), 1.32-1.45 (5H, m),1.55-1.65 (2H, m), 2.02 (3H, d, J=1.2 Hz), 2.22-2.35 (2H, m), 2.98-3.03(2H, m), 3.37-3.42 (2H, m), 3.54 (2H, t, J=6.9 Hz), 3.80 (2H, t, J=4.8Hz), 4.14 (2H, t, J=4.8 Hz), 4.27 (2H, q, J=6.9 Hz), 6.79 (1H, d, J=8.4Hz), 6.95 (2H, d, J=8.7 Hz), 7.30 (1H, d, J=2.1 Hz), 7.38 (1H, dd,J=8.4, 2.1 Hz), 7.43 (2H, d, J=8.7 Hz), 7.81 (1H, s).

Elementary analysis C₃₀H₄₁NO₄, Calcd. C, 75.12; H, 8.62; N, 2.92. FoundC, 74.83; H, 8.33; N, 2.77.

REFERENCE EXAMPLE 143

Ethyl(2E)-3-[4′-(2-butoxyethoxy)-4-(3,4-dimethylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylate(1.04 g) was dissolved in THF (35 ml) and methanol (35 ml). Then, a 1 Naqueous sodium hydroxide solution (8.7 ml) was added thereto, and themixture was stirred for 3 hours at 90° C. After adding water at 0° C.,the resulting mixture was neutralized with 1 N hydrochloric acid andextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waswashed with hexane to give(2E)-3-[4′-(2-butoxyethoxy)-4-(3,4-dimethylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methylacrylicacid (0.97 g) as yellow crystals.

m.p. 126.3-128.3° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.87-0.99 (9H, m), 1.33-1.45 (2H, m),1.56-1.65 (2H, m), 2.05 (3H, d, J=1.2 Hz), 2.27-2.37 (2H, m), 3.00-3.05(2H, m), 3.40-3.45 (2H, m), 3.55 (2H, t, J=6.9 Hz), 3.80 (2H, t, J=4.8Hz), 4.15 (2H, t, J=4.8 Hz), 6.83 (1H, d, J=7.2 Hz), 6.97 (2H, d, J=8.7Hz), 7.34 (1H, d, J=1.8 Hz), 7.40 (1H, dd, J=7.2, 1.8 Hz), 7.44 (2H, d,J=8.7 Hz), 7.97 (1H, s).

Elementary analysis C₂₈H₃₇NO₄, Calcd. C, 74.47; H, 8.26; N, 3.10. FoundC, 74.32; H, 8.44; N, 2.87.

REFERENCE EXAMPLE 144

To 5-bromo-2-hydroxynicotinic acid (40 g) was added dropwise thionylchloride (200 ml) at 0° C. Next, DMF (12.5 ml) was added dropwisethereto at 0° C., and the resulting mixture was refluxed for 2 hours.After returning to room temperature, excess thionyl chloride wasdistilled off under reduced pressure. To the resulting residue was addeddropwise methanol (450 ml) at 0° C., and the solvent was distilled offunder reduced pressure. To the resulting residue was added an aqueoussaturated sodium hydrogen carbonate solution at 0° C., which wasneutralized and then extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over magnesium sulfate. Thesolvent was distilled off under reduced pressure, and then the resultingresidue was purified by silica gel column chromatography (hexane:ethylacetate=9:1) to give methyl 5-bromo-2-chloronicotinate (39.5 g) ascolorless crystals.

¹H-NMR (300 MHz, CDCl₃) δ 3.97 (3H, s), 8.28 (1H, d, J=2.4 Hz), 8.56(1H, d, J=2.4 Hz).

Elementary analysis C₇H₅NO₂ClBr, Calcd. C, 33.57; H, 2.01; N, 5.59.Found C, 33.53; H, 2.21; N, 5.66.

REFERENCE EXAMPLE 145

To a suspension of sodium hydride (60% oily material, 48 mg) in DMF (5ml) was added pyrrolidine (0.1 ml) at 0° C., and the mixture was stirredfor 1 hour at room temperature under a nitrogen atmosphere. Next, asolution of methyl 5-bromo-2-chloronicotinate (100 mg) in DMF (5 ml) wasadded dropwise at thereto 0° C. under a nitrogen atmosphere, and themixture was stirred overnight at 75° C. After returning to roomtemperature, 0.1 N hydrochloric acid was added thereto, which wasacidified and then extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over magnesium sulfate. Thesolvent was distilled off under reduced pressure, and then the resultingresidue was washed with hexane to give5-bromo-2-pyrrolidin-1-ylnicotinic acid (67 mg) as colorless crystals.

¹H-NMR (300 MHz, CDCl₃) δ 2.01-2.11 (4H, m), 3.38-3.43 (4H, m), 8.35(1H, d, J=2.4 Hz), 8.43 (1H, d, J=2.4 Hz).

Elementary analysis C₁₀H₁₁N₂O₂Br, Calcd. C, 44.30; H, 4.09; N, 10.33.Found C, 44.34; H, 4.06; N, 10.29.

REFERENCE EXAMPLE 146

To a solution of 5-bromo-2-pyrrolidin-1-ylnicotinic acid (800 mg),N,O-dimethylhydroxylamine hydrochloride (375 mg) and1-hydroxybenzotriazole monohydrate (588 mg) in DMF (20 ml) was addedtriethylamine (0.54 ml) and a catalytic amount of4-(N,N-dimethylamino)pyridine, followed by adding1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (736 mg),and the mixture was stirred overnight under a nitrogen atmosphere. Waterwas added thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with an aqueous saturated sodium hydrogencarbonate solution, water and saturated brine, and then dried overmagnesium sulfate. The solvent was distilled off under reduced pressure,and then the resulting residue was purified by silica gel columnchromatography (hexane:ethyl acetate=8:1→hexane:ethyl acetate=1:1) andrecrystallized from hexane-ethyl acetate to give5-bromo-N-methoxy-N-methyl-2-pyrrolidin-1-ylnicotinamide (812 mg) ascolorless crystals.

m.p. 94.0-96.0° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.91-1.96 (4H, m), 3.29 (3H, s), 3.37-3.41(4H, m), 3.57 (3H, br), 7.49 (1H, d, J=2.4 Hz), 8.17 (1H, d, J=2.4 Hz).

Elementary analysis C₁₂H₁₆N₃O₂Br, Calcd. C, 45.87; H, 5.13; N, 13.37.Found C, 45.83; H, 5.07; N, 13.22.

REFERENCE EXAMPLE 147

To a solution of lithium aluminum hydride (74.2 mg) in tetrahydrofuran(10 ml) was added dropwise a solution of5-bromo-N-methoxy-N-methyl-2-pyrrolidin-1-ylnicotinamide (615 mg) intetrahydrofuran (10 ml) at 0° C. under a nitrogen atmosphere, and thenthe mixture was returned to room temperature and stirred for 30 minutes.Water (0.08 ml), an aqueous 15% sodium hydroxide solution (0.08 ml) andwater (0.24 ml) were sequentially added thereto at 0° C., and then themixture was returned to room temperature and stirred overnight. Afteradding magnesium sulfate, the insolubles were removed by filtration. Thesolvent was distilled off under reduced pressure to give5-bromo-2-pyrrolidin-1-ylnicotinaldehyde (470 mg) as a yellow oilymaterial.

¹H-NMR (300 MHz, CDCl₃) δ 1.96-2.01 (4H, m), 3.50-3.54 (4H, m), 8.00(1H, d, J=2.4 Hz), 8.30 (1H, d, J=2.4 Hz), 9.95 (1H, s).

REFERENCE EXAMPLE 148

A suspension of 5-bromo-2-pyrrolidin-lylnicotinaldehyde (450 mg),4-(2-butoxyethoxy)phenylboric acid (545 mg) and potassium carbonate (634mg) in toluene (20 ml), ethanol (2 ml) and water (2 ml) was stirred for1 hour under an argon atmosphere. Then,tetrakis(triphenylphosphine)palladium (102 mg) was added thereto, andthe resulting mixture was refluxed for 7 hours. After returning to roomtemperature, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=9:1→hexane:ethylacetate=2:1) and recrystallized from hexane-ethyl acetate to give5-[4-(2-butoxyethoxy)phenyl]-2-pyrrolidin-1-ylnicotinaldehyde (558 mg)as yellow crystals.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.5 Hz), 1.33-1.47 (2H, m),1.55-1.66 (2H, m), 1.99-2.05 (4H, m), 3.51-3.62 (6H, m), 3.81 (2H, t,J=5.1 Hz), 4.15 (2H, t, J=5.1 Hz), 7.01 (2H, d, J=9.0 Hz), 7.46 (2H, d,J=9.0 Hz), 8.11 (1H, d, J=2.4 Hz), 8.56 (1H, d, J=2.4 Hz), 10.11 (1H,s).

Elementary analysis C₂₂H₂₈N₂O₃, Calcd. C, 71.71; H, 7.66; N, 7.60. FoundC, 71.63; H, 7.71; N, 7.42.

REFERENCE EXAMPLE 149

To a suspension of sodium hydride (42 mg) in toluene (10 ml) was addeddropwise a solution of ethyl diethylphosphonoacetate (0.189 ml) intoluene (10 ml) at 0° C. under a nitrogen atmosphere, and the mixturewas stirred as such for 1 hour. Next, a solution of5-[4-(2-butoxyethoxy)phenyl]-2-pyrrolidin-1-ylnicotinaldehyde (270 mg)in toluene (10 ml) was added dropwise thereto at 0° C. under a nitrogenatmosphere, and then the resulting mixture was refluxed for 3 hours.After removing from the oil bath, water was added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waspurified by basic silica gel column chromatography (hexane:ethylacetate=13:1→hexane ethyl acetate=1:1) to give ethyl(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-pyrrolidin-1-ylpyridin-3-yl]acrylate(229 mg) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 0.96-1.43 (5H, m),1.51-1.64 (2H, m), 1.92-1.97 (4H, m), 3.53-3.63 (6H, m), 3.81 (2H, t,J=5.1 Hz), 4.16 (2H, t, J=5.1 Hz), 4.26 (2H, q, J=7.2 Hz), 6.23 (1H, d,J=15.6 Hz), 6.99 (2H, d, J=8.7 Hz), 7.43 (2H, d, J=8.7 Hz), 7.76 (1H, d,J=1.8 Hz), 8.01 (1H, d, J=15.6 Hz), 8.37 (1H, d, J=1.8 Hz).

REFERENCE EXAMPLE 150

Ethyl(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-pyrrolidin-1-ylpyridin-3-yl]acrylate(215 mg) was dissolved in THF (6 ml) and methanol (6 ml). Then, a 1 Naqueous sodium hydroxide solution (2.0 ml) was added thereto, and themixture was stirred for 3 hours at 90° C. After adding water at 0° C.,the resulting mixture was neutralized with 1 N hydrochloric acid andextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waswashed with hexane to give(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-pyrrolidin-1-ylpyridin-3-yl]acrylicacid (200 mg) as yellow crystals.

m.p. 162.5-164.5° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.35-1.47 (2H, m),1.52-1.70 (2H, m), 1.93-1.98 (4H, m), 3.55 (2H, t, J=6.6 Hz), 3.58-3.63(4H, m), 3.81 (2H, t, J=4.8 Hz), 4.16 (2H, t, J=4.8 Hz), 6.24 (1H, d,J=15.6 Hz), 7.00 (2H, d, J=8.7 Hz), 7.44 (2H, d, J=8.7 Hz), 7.79 (1H, d,J=2.4 Hz), 8.10 (1H, d, J=15.6 Hz), 8.39 (1H, d, J=2.4 Hz).

Elementary analysis C₂₄H₃₀N₂O₄, Calcd. C, 70.22; H, 7.37; N, 6.82. FoundC, 69.97; H, 7.22; N, 6.61.

REFERENCE EXAMPLE 151

To a suspension of sodium hydride (42 mg) in toluene (10 ml) was addeddropwise a solution of triethyl 2-phosphonopropionate (0.204 ml) intoluene (10 ml) at 0° C. under a nitrogen atmosphere, and the mixturewas stirred as such for 1 hour. Next, a solution of5-[4-(2-butoxyethoxy)phenyl]-2-pyrrolidin-1-ylnicotinaldehyde (270 mg)in toluene (10 ml) was added dropwise thereto at 0° C. under a nitrogenatmosphere, and then the resulting mixture was refluxed for 3 hours.After removing from the oil bath, water was added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waspurified by basic silica gel column chromatography (hexane:ethylacetate=9:1→hexane:ethyl acetate=6:1) to give ethyl(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-pyrrolidin-1-ylpyridin-3-yl]-2-methylacrylate(275 mg) as a green oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=8.1 Hz), 1.33-1.50 (5H, m),1.55-1.65 (2H, m), 1.84-1.94 (4H, m), 1.99 (3H, d, J=1.5 Hz), 3.47-3.57(6H, m), 3.80 (2H, t, J=4.5 Hz), 4.15 (2H, t, J=4.5 Hz), 4.28 (2H, q,J=6.9 Hz), 6.99 (2H, d, J=9.0 Hz), 7.41 (2H, d, J=9.0 Hz), 7.50 (1H, d,J=2.4 Hz), 7.77 (1H, s), 8.33 (1H, d, J=2.4 Hz).

REFERENCE EXAMPLE 152

Ethyl(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-pyrrolidin-1-ylpyridin-3-yl]-2-methylacrylate(265 mg) was dissolved in THF (7 ml) and methanol (7 ml). Then, a 1 Naqueous sodium hydroxide solution (2.34 ml) was added thereto, and themixture was stirred for 3 hours at 90° C. After adding water at 0° C.,the resulting mixture was neutralized with 1 N hydrochloric acid andextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waswashed with hexane to give(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-pyrrolidin-1-ylpyridin-3-yl]-2-methylacrylicacid (184 mg) as yellow crystals.

m.p. 106.0-107.0° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.5 Hz), 1.33-1.46 (2H, m),1.56-1.65 (2H, m), 1.91-1.95 (4H, m), 2.02 (3H, d, J=1.2 Hz), 3.50-3.57(6H, m), 3.80 (2H, t, J=4.8 Hz), 4.16 (2H, t, J=4.8 Hz), 6.99 (2H, d,J=8.7 Hz), 7.42 (2H, d, J=8.7 Hz), 7.53 (1H, d, J=1.8 Hz), 7.90 (1H, s),8.35 (1H, d, J=1.8 Hz).

Elementary analysis C₂₅H₃₂N₂O₄, Calcd. C, 70.73; H, 7.60; N, 6.60. FoundC, 70.65; H, 7.86; N, 6.42.

REFERENCE EXAMPLE 153

To a suspension of calcium chloride (33.6 g) in ethanol (250 ml) andtetrahydrofuran (250 ml) was added sodium borohydride (23.0 g) at 0° C.portionwise. After stirring for 1 hour at 0° C. with a calcium chloridetube equipped, methyl 5-bromo-2-chloronicotinate (19.0 g) was addedthereto, and the mixture was stirred as such overnight at 0° C. Thereaction mixture was acidified with 2.5 N hydrochloric acid at 0° C.,which was returned to room temperature and stirred for 1 hour. Afterneutralization with an aqueous sodium hydrogen carbonate solution, theinsolubles were removed by filtration. The solvent was distilled offunder reduced pressure, and then the resulting residue was purified bysilica gel column chromatography (hexane:ethyl acetate=9:1→hexane:ethylacetate=4:1) to give (5-bromo-2-chloropyridin-3-yl)methanol (15.0 g) ascolorless crystals.

m.p. 86.7-87.5° C.

¹H-NMR (300 MHz, CDCl₃) δ 4.77 (2H, s), 8.04 (1H, d, J=2.4 Hz), 8.36(1H, d, J=2.4 Hz).

Elementary analysis C₆H₅NOClBr, Calcd. C, 32.39; H, 2.27; N, 6.30. FoundC, 32.38; H, 2.24; N, 6.28.

REFERENCE EXAMPLE 154

To a solution of oxalyl chloride (1.98 ml) in dichloromethane (20 ml)was added dropwise a solution of DMSO (3.45 ml) in dichloromethane (30ml) at −78° C. under a nitrogen atmosphere. The mixture was stirred assuch for 10 minutes, and then a solution of5-bromo-2-chloropyridin-3-yl)methanol (3.6 g) in dichloromethane (35 ml)was added dropwise thereto. The mixture was stirred as such for 10minutes, and then triethylamine (13.5 ml) was added dropwise thereto.After stirring as such for 10 minutes, the resulting mixture wasreturned to room temperature and stirred for 1 hour. To the reactionsolution was added water, followed by separation. The organic layer waswashed with water and saturated brine, and dried over magnesium sulfate.The solvent was distilled off under reduced pressure, and then theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=6:1) to give 5-bromo-2-chloronicotinaldehyde (3.4g) as colorless crystals.

m.p. 88.0-89.0° C.

¹H-NMR (300 MHz, CDCl₃) δ 8.33 (1H, d, J=2.7 Hz), 8.67 (1H, d, J=2.7Hz), 10.38 (1H, s).

Elementary analysis C₆H₃NOClBr, Calcd. C, 32.69; H, 1.37; N, 6.35. FoundC, 32.51; H, 1.33; N, 6.18.

REFERENCE EXAMPLE 155

A suspension of 5-bromo-2-chloronicotinaldehyde (1.2 g),3-methylpyrrolidine (928 mg) and sodium carbonate (1.16 g) in DMSO (40ml) and water (20 ml) was stirred for 2 hours at 75° C. under a nitrogenatmosphere. After returning to room temperature, water was added theretoand the mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, and dried over magnesium sulfate.The solvent was distilled off under reduced pressure, and then theresulting residue was separated and purified by silica gel columnchromatography (hexane:ethyl acetate=20:1→hexane:ethyl acetate=4:1). Theresulting solids were washed with hexane to give5-bromo-2-(3-methylpyrrolidin-1-yl)nicotinaldehyde (761 mg) as yellowcrystals.

m.p. 72.0-73.0° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.13 (3H, d, J=6.6 Hz), 1.53-1.67 (1H, m),2.07-2.16 (1H, m), 2.28-2.41 (1H, m), 3.17-3.24 (1H, m), 3.46-3.56 (2H,m), 3.61-3.70 (1H, m), 8.01 (1H, d, J=2.4 Hz), 8.31 (1H, d, J=2.4 Hz),9.96 (1H, s).

Elementary analysis C₁₁H₁₃N₂OBr, Calcd. C, 49.09; H, 4.87; N, 10.41.Found C, 49.07; H, 4.88; N, 10.29.

REFERENCE EXAMPLE 156

To a suspension of sodium hydride (155 mg) in toluene (10 ml) was addeddropwise a solution of triethyl 2-phosphonopropionate (0.76 ml) intoluene (10 ml) at 0° C. under a nitrogen atmosphere, and the mixturewas stirred as such for 1 hour. Next, a solution of5-bromo-2-(3-methylpyrrolidin-1-yl)nicotinaldehyde (730 mg) in toluene(10 ml) was added dropwise thereto at 0° C. under a nitrogen atmosphere,and the resulting mixture was refluxed for 3 hours. After removing fromthe oil bath, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was purified by basicsilica gel column chromatography (hexane:ethyl acetate=19:1→hexane:ethylacetate=4:1) to give ethyl(2E)-3-[5-bromo-2-(3-methylpyrrolidin-1-yl)pyridin-3-yl]-2-methylacrylate(914 mg) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 1.07 (3H, d, J=6.6 Hz), 1.34 (3H, t, J=6.9Hz), 1.45-1.62 (1H, m), 1.94 (3H, d, J=1.5 Hz), 1.96-2.08 (1H, m),2.20-2.35 (1H, m), 3.01-3.07 (1H, m), 3.42-3.55 (3H, m), 4.26 (2H, q,J=6.9 Hz), 7.37 (1H, d, J=2.4 Hz), 7.60 (1H, s), 8.10 (1H, d, J=2.4 Hz).

REFERENCE EXAMPLE 157

A suspension of ethyl(2E)-3-[5-bromo-2-(3-methylpyrrolidin-1-yl)pyridin-3-yl]-2-methylacrylate(880 mg), 4-(2-butoxyethoxy)phenylboric acid (774 mg) and potassiumcarbonate (898 mg) in toluene (15 ml), ethanol (1.5 ml) and water (1.5ml) was stirred for 1 hour under an argon atmosphere. Then,tetrakis(triphenylphosphine)palladium (144 mg) was added thereto, andthe resulting mixture was refluxed for 5 hours. After returning to roomtemperature, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=19:1→hexane:ethylacetate=4:1) to give ethyl(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-(3-methylpyrrolidin-1-yl)pyridin-3-yl]-2-methylacrylate(970 mg) as a green oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.5 Hz), 1.10 (3H, d, J=6.6Hz), 1.32-1.65 (8H, m), 1.98-2.10 (4H, m), 2.20-2.40 (1H, m), 3.09-3.16(1H, m), 3.47-3.63 (5H, m), 3.79 (2H, t, J=4.8 Hz), 4.16 (2H, t, J=4.8Hz), 4.27 (2H, q, J=7.5 Hz), 6.97 (2H, d, J=8.7 Hz), 7.40 (2H, d, J=8.7Hz), 7.48 (1H, d, J=2.4 Hz), 7.75 (1H, s), 8.31 (1H, d, J=2.4 Hz).

REFERENCE EXAMPLE 158

Ethyl(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-(3-methylpyrrolidin-1-yl)pyridin-3-yl]-2-methylacrylate(950 mg) was dissolved in THF (32 ml) and methanol (32 ml). Then, a 1 Naqueous sodium hydroxide solution (8.14 ml) was added thereto, and themixture was stirred for 3 hours at 90° C. After adding water at 0° C.,the resulting mixture was neutralized with 1 N hydrochloric acid andextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waspurified by silica gel column chromatography (hexane:ethylacetate=1:1→ethyl acetate). The resulting solids were washed with hexaneto give(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-(3-methylpyrrolidin-1-yl)pyridin-3-yl]-2-methylacrylicacid (758 mg) as yellow crystals.

m.p. 106.5-108.5° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.5 Hz), 1.11 (3H, d, J=6.6Hz), 1.33-1.46 (2H, m), 1.51-1.66 (3H, m), 1.95-2.10 (4H, m), 2.22-2.40(1H, m), 3.12-3.18 (1H, m), 3.50-3.64 (5H, m), 3.81 (2H, t, J=4.8 Hz),4.16 (2H, t, J=4.8 Hz), 6.99 (2H, d, J=8.7 Hz), 7.42 (2H, d, J=8.7 Hz),7.53 (1H, d, J=2.4 Hz), 7.90 (1H, s), 8.35 (1H, d, J=2.4 Hz).

Elementary analysis C₂₆H₃₄N₂O₄, Calcd. C, 71.21; H, 7.81; N, 6.39. FoundC, 71.07; H, 7.74; N, 6.13.

REFERENCE EXAMPLE 159

A suspension of 5-bromo-2-chloronicotinaldehyde (1.5 g),3-hydroxymethylpyrrolidine hydrochloride (1.87 g) and sodium carbonate(1.8 g) in DMSO (45 ml) and water (22.5 ml) was heated for 2 hours at75° C. under a nitrogen atmosphere. After returning to room temperature,water was added thereto and the mixture was extracted with ethylacetate. The organic layer was washed with water and saturated brine,and dried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was separated andpurified by silica gel column chromatography (hexane:ethyl acetate2:1→ethyl acetate). The resulting solids were washed with hexane to give5-bromo-2-[3-(hydroxymethyl)pyrrolidin-1-yl]nicotinaldehyde (1.67 g) asyellow crystals.

m.p. 84.0-85.5° C.

¹H-NMR (300 MHz, CDCl₃) δ 1.47-1.60 (1H, m), 1.78-1.90 (1H, m),2.08-2.20 (1H, m), 2.49-2.59 (1H, m), 3.42-3.74 (6H, m), 8.02 (1H, d,J=2.4 Hz), 8.32 (1H, d, J=2.4 Hz), 9.96 (1H, s).

Elementary analysis C₁₁H₁₃N₂O₂Br, Calcd. C, 46.33; H, 4.60; N, 9.82.Found C, 46.50; H, 4.57; N, 9.74.

REFERENCE EXAMPLE 160

To a solution of5-bromo-2-[3-(hydroxymethyl)pyrrolidin-1-yl]nicotinaldehyde (1.75 g) inpyridine (10 ml) was added dropwise acetic anhydride (2.32 ml) at 0° C.under a nitrogen atmosphere. The mixture was returned to roomtemperature and stirred for 3 hours. Then, water was added thereto at 0°C., and further added sodium carbonate, which was neutralized. Afterextraction with ethyl acetate, the organic layer was washed with waterand saturated brine, and the solvent was distilled off under reducedpressure. The resulting residue was purified by silica gel columnchromatography (hexane:ethyl acetate=3:1→hexane:ethyl acetate=1:1) togive [1-(5-bromo-3-formylpyridin-2-yl)pyrrolidin-3-yl]methyl acetate(1.76 g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 1.74-1.86 (1H, m), 2.07 (3H, s), 2.12-2.17(1H, m), 2.60-2.70 (1H, m), 3.38-3.45 (1H, m), 3.50-3.70 (3H, m),4.02-4.21 (2H, m), 8.02 (1H, d, J=1.8 Hz), 8.32 (1H, d, J=1.8 Hz), 9.95(1H, s).

REFERENCE EXAMPLE 161

A solution of [1-(5-bromo-3-formylpyridin-2-yl)pyrrolidin-3-yl]methylacetate (1.6 g), tert-butyl 2-(triphenylphosphoranylidene)propanoate(2.48 g) in toluene (50 ml) was refluxed for 3 hours under a nitrogenatmosphere. After returning to room temperature, water was added theretoand the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine, and dried over magnesium sulfate. Thesolvent was distilled off under reduced pressure, and then the resultingresidue was purified by basic silica gel column chromatography (hexaneethyl acetate=15:1→hexane:ethyl acetate=4:1) to give tert-butyl(2E)-3-[2-[3-(acetoxymethyl)pyrrolidin-1-yl]-5-bromopyridin-3-yl]-2-methylacrylate(1.44 g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 1.53 (9H, s), 1.67-1.76 (1H, m), 1.90 (3H, d,J=1.5 Hz), 2.00-2.10 (4H, m), 2.52-2.61 (1H, m), 3.25-3.31 (1H, m),3.45-3.50 (2H, m), 3.55-3.61 (1H, m), 4.00-4.15 (2H, m), 7.38 (1H, d,J=3.0 Hz), 7.48 (1H, s), 8.10 (1H, d, J=3.0 Hz).

REFERENCE EXAMPLE 162

A suspension of tert-butyl(2E)-3-[2-[3-(acetoxymethyl)pyrrolidin-1-yl]-5-bromopyridin-3-yl]-2-methylacrylate(1.4 g), 4-(2-butoxyethoxy)phenylboric acid (986 mg) and potassiumcarbonate (1.15 g) in toluene (25 ml), ethanol (2.5 ml) and water (2.5ml) was stirred for 1 hour under an argon atmosphere. Then,tetrakis(triphenylphosphine)palladium (184 mg) was added thereto, andthe resulting mixture was refluxed for 6 hours. After returning to roomtemperature, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=9:1→hexane:ethylacetate=3:1) to give tert-butyl(2E)-3-[2-[3-(acetoxymethyl)pyrrolidin-1-yl]-5-[4-(2-butoxyethoxy)phenyl]pyridin-3-yl]-2-methylacrylate(1.41 g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.5 Hz), 1.30-1.80 (14H, m),1.95 (3H, d, J=1.5 Hz), 2.00-2.20 (4H, m), 2.50-2.65 (1H, m), 3.34-3.40(1H, m), 3.53-3.57 (4H, m), 3.63-3.69 (1H, m), 3.80 (2H, t, J=4.5 Hz),4.03-4.18 (4H, m), 6.99 (2H, d, J=9.0 Hz), 7.41 (2H, d, J=9.0 Hz), 7.51(1H, d, J=2.1 Hz), 7.64 (1H, s), 8.32 (1H, d, J=2.1 Hz).

REFERENCE EXAMPLE 163

tert-Butyl(2E)-3-[2-[3-(acetoxymethyl)pyrrolidin-1-yl]-5-[4-(2-butoxyethoxy)phenyl]pyridin-3-yl]-2-methylacrylate(1.25 g) was dissolved in ethyl acetate (17 ml). Then, a 4 Nhydrochloric acid-ethyl acetate solution (17 ml) was added thereto, andthe mixture was stirred overnight under a nitrogen atmosphere. Afteradding water at 0° C., potassium carbonate (4.7 g) was added thereto,and the mixture was extracted with ethyl acetate. The organic layer waswashed with water and saturated brine, and dried over magnesium sulfate.The solvent was distilled off under reduced pressure, and then theresulting residue was purified by silica gel column chromatography(hexane:ethyl acetate=1:1→ethyl acetate). The resulting solids werewashed with hexane-diisopropyl ether to give(2E)-3-[2-[3-(acetoxymethyl)pyrrolidin-1-yl]-5-[4-(2-butoxyethoxy)phenyl]pyridin-3-yl]-2-methylacrylicacid (823 mg) as yellow crystals.

m.p. 82.2-84.2° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.33-1.45 (2H, m),1.50-1.80 (3H, m), 2.02-2.17 (7H, m), 2.50-2.67 (1H, m), 3.35-3.41 (1H,m), 3.49-3.59 (4H, m), 3.63-3.69 (1H, m), 3.81 (2H, t, J=4.8 Hz),4.04-4.17 (4H, m), 7.00 (2H, d, J=8.7 Hz), 7.42 (2H, d, J=8.7 Hz), 7.54(1H, d, J=2.1 Hz), 7.87 (1H, s), 8.35 (1H, d, J=1.5 Hz).

Elementary analysis C₂₈H₃₆N₂O₆, Calcd. C, 67.72; H, 7.31; N, 5.64. FoundC, 67.64; H, 7.26; N, 5.48.

REFERENCE EXAMPLE 164

A suspension of 5-bromo-2-chloronicotinaldehyde (1.5 g),3,4-dimethylpyrrolidine hydrochloride (1.85 g) and sodium carbonate (1.8g) in DMSO (45 ml) and water (22.5 ml) was stirred for 3 hours at 80° C.under a nitrogen atmosphere. After returning to room temperature, waterwas added thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over magnesiumsulfate. The solvent was distilled off under reduced pressure, which wasseparated and purified by silica gel column chromatography (hexane:ethylacetate=19:1 hexane:ethyl acetate=4:1). The resulting residuerecrystallized from hexane-ethyl acetate to give5-bromo-2-(3,4-dimethylpyrrolidin-1-yl)nicotinaldehyde (1.56 g) asyellow crystals.

m.p. 98.5-99.5° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.98 (6H, d, J=6.6 Hz), 2.31-2.41 (2H, m),3.22-3.28 (2H, m), 3.59-3.65 (2H, m), 8.00 (1H, d, J=2.4 Hz), 8.29 (1H,d, J=2.4 Hz), 9.95 (1H, s).

Elementary analysis C₁₂H₁₅N₂OBr, Calcd. C, 50.90; H, 5.34; N, 9.89.Found C, 50.93; H, 5.35; N, 9.82.

REFERENCE EXAMPLE 165

To a suspension of sodium hydride (303 mg) in toluene (20 ml) was addeddropwise a solution of triethyl 2-phosphonopropionate (1.48 ml) intoluene (20 ml) at 0° C. under a nitrogen atmosphere, and the mixturewas stirred as such for 1 hour. Next, a solution of5-bromo-2-(3,4-dimethylpyrrolidin-1-yl)nicotinaldehyde (1.5 g) intoluene (20 ml) was added dropwise thereto at 0° C. under a nitrogenatmosphere, and then the resulting mixture was refluxed for 3 hours.After removing from the oil bath, water was added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waspurified by basic silica gel column chromatography (hexane ethylacetate=10:1→hexane:ethyl acetate=1:1) to give ethyl(2E)-3-[5-bromo-2-(3,4-dimethylpyrrolidin-1-yl)pyridin-3-yl]-2-methylacrylate(1.94 g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.94 (6H, d, J=6.6 Hz), 1.34 (3H, t, J=7.2Hz), 1.93 (3H, d, J=1.5 Hz), 2.20-2.30 (2H, m), 3.11-3.17 (2H, m),3.48-3.54 (2H, m), 4.26 (2H, q, J=7.2 Hz), 7.37 (1H, d, J=2.1 Hz), 7.60(1H, s), 8.09 (1H, d, J=2.1 Hz).

REFERENCE EXAMPLE 166

A suspension of ethyl(2E)-3-[5-bromo-2-(3,4-dimethylpyrrolidin-1-yl)pyridin-3-yl]-2-methylacrylate(1.9 g), 4-(2-butoxyethoxy)phenylboric acid (1.6 g) and potassiumcarbonate (1.87 g) in toluene (30 ml), ethanol (3 ml) and water (3 ml)was stirred for 1 hour under an argon atmosphere. Then,tetrakis(triphenylphosphine)palladium (300 mg) was added thereto, andthe resulting mixture was refluxed for 5 hours. After returning to roomtemperature, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=19:1→hexane:ethylacetate=4:1) to give ethyl(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-(3,4-dimethylpyrrolidin-1-yl)pyridin-3-yl]-2-methylacrylate(1.92 g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.90-0.98 (9H, m), 1.33-1.45 (5H, m),1.55-1.65 (2H, m), 1.98 (3H, d, J=1.2 Hz), 2.22-2.37 (2H, m), 3.20-3.25(2H, m), 3.53-3.62 (4H, m), 3.80 (2H, t, J=4.8 Hz), 4.15 (2H, t, J=4.8Hz), 4.28 (2H, q, J=7.2 Hz), 6.98 (2H, d, J=8.7 Hz), 7.41 (2H, d, J=8.7Hz), 7.49 (1H, d, J=2.4 Hz), 7.76 (1H, s), 8.32 (1H, d, J=2.4 Hz).

REFERENCE EXAMPLE 167

Ethyl(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-(3,4-dimethylpyrrolidin-1-yl)pyridin-3-yl]-2-methylacrylate(1.9 g) was dissolved in THF (60 ml) and methanol (60 ml). Then, a 1 Naqueous sodium hydroxide solution (15.8 ml) was added thereto, and themixture was stirred for 4 hours at 90° C. After adding water at 0° C.,the resulting mixture was neutralized with 1 N hydrochloric acid andextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure, and then the resulting residue waswashed with hexane to give(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-(3,4-dimethylpyrrolidin-1-yl)pyridin-3-yl]-2-methylacrylicacid (1.51 g) as yellow crystals.

m.p. 90.0-92.0° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.5 Hz), 1.03 (6H, d, J=6.3Hz), 1.33-1.45 (2H, m), 1.56-1.66 (2H, m), 2.03 (3H, d, J=1.2 Hz),2.38-2.50 (2H, m), 3.52-3.60 (4H, m), 3.80 (2H, t, J=4.8 Hz), 3.85-4.00(2H, m), 4.15 (2H, t, J=4.8 Hz), 7.00 (2H, d, J=8.7 Hz), 7.40 (2H, d,J=8.7 Hz), 7.75 (1H, s), 7.80 (1H, s), 8.44 (1H, s).

Elementary analysis C₂₇H₃₆N₂O₄.0.25H₂O, Calcd. C, 70.95; H, 8.05; N,6.13. Found C, 71.17; H, 7.67; N, 6.08.

REFERENCE EXAMPLE 168

To a solution of hydrazine monohydrate (9.66 g) in ethanol (100 ml) wasslowly added dropwise ethyl glycolate (20.09 g) at room temperaturewhile the temperature of the reaction system was maintained at 10° C. orlower. After stirring the mixture for 4 hours at room temperature,propyl isothiocyanate (20 ml) was slowly added dropwise thereto whilethe temperature of the reaction system was maintained at 10° C. orlower. After stirring for 64 hours at 40° C., the resulting mixture wascooled to room temperature, and ice water (50 ml) was added thereto. Themixture was stirred for 15 minutes and a 5 N aqueous sodium hydroxidesolution (40 ml) was then added thereto, which was stirred for 4 hoursat 60° C. Concentrated hydrochloric acid was added dropwise thereto at0° C. until the pH reached 6, and the precipitated crystals were removedby filtration. After concentration under reduced pressure, theprecipitated crystals were collected by filtration. The crystals werewashed with water to give3-hydroxymethyl-5-mercapto-4-propyl-4H-1,2,4-triazole (23.45 g) ascolorless crystals. To a mixture of 90% nitric acid (18 ml) and water(26 ml) was added sodium nitrite (0.07 g), followed by slowly adding3-hydroxymethyl-5-mercapto-4-propyl-4H-1,2,4-triazole (10 g) at 45° C.over 0.5 hour. After cooling to room temperature, sodium carbonate wasslowly added thereto at 0° C. until the pH reached 7. Afterconcentration under reduced pressure, methanol was added thereto, andthe precipitates were removed by filtration. After concentration underreduced pressure, dichloromethane was added thereto, and theprecipitates were removed by filtration. The filtrate was concentratedto give 3-hydroxymethyl-4-propyl-4H-1,2,4-triazole (5.95 g) as a crudeproduct. To 3-hydroxymethyl-4-propyl-4H-1,2,4-triazole (5.95 g) wasslowly added thionyl chloride (40 ml) at 0° C. The mixture was heatedunder reflux for 1 hour, and then concentrated under reduced pressure.To the residue was added ethanol, and further concentrated. To theresidue was added ethyl acetate and a small amount of ethanol, and theprecipitated crystals were collected by filtration. The crystals werewashed with ethyl acetate to give3-chloromethyl-4-propyl-4H-1,2,4-triazole hydrochloride (5.43 g) as paleyellow crystals.

m.p. 91-94° C.

¹H-NMR (200 MHz, CDCl₃) δ 0.80 (3H, t, J=7.3 Hz), 1.73-1.94 (2H, m),4.11 (2H, t, J=7.4 Hz), 5.10 (2H, s), 9.26 (1H, s).

IR (KBr) 3353, 1574, 1537, 1470, 1331, 1204, 1177, 957 cm⁻¹

Elementary analysis C₆H₁₁N₃Cl₂.0.25H₂O, Calcd. C, 35.93; H, 5.78; N,20.95. Found. C, 36.13; H, 5.77; N, 21.23.

REFERENCE EXAMPLE 169

To a solution of aminothiophenol (2.9 g) and triethylamine (14.2 ml) intetrahydrofuran (70 ml) was added dropwise a solution of3-(chloromethyl)-4-propyl-4H-1,2,4-triazole hydrochloride (5.0 g) inmethanol (30 ml) at 0° C. under a nitrogen atmosphere. The mixture wasreturned to room temperature and stirred for 4 hours, and then thesolvent was distilled off under reduced pressure. To the resultingresidue was added an aqueous sodium hydrogen carbonate solution, and themixture was extracted with ethyl acetate three times. The organic layerswere combined and dried over magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resulting residue was purifiedby basic silica gel column chromatography (ethyl acetate→methanol:ethylacetate=1:10) to give4-[[(4-propyl-4H-1,2,4-triazole-3-yl)methyl]sulfanyl]aniline (5.39 g) asa brown oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.98 (3H, t, J=7.2 Hz), 1.77-1.90 (2H, m),3.74 (2H, br), 3.91 (2H, t, J=7.5 Hz), 4.08 (2H, s), 6.56 (2H, d, J=8.7Hz), 7.12 (2H, d, J=8.7 Hz), 8.06 (1H, s).

REFERENCE EXAMPLE 170

A mixture of potassium thiocyanate (119.2 g), dihydroxyacetone dimer(73.9 g) and propylamine hydrochloride (100 g) was portionwise added toa mixed solution of acetic acid (89 ml) and 1-butanol (590 ml). Themixture was stirred at room temperature for 1 day, and then water (118ml) was added thereto, followed by stirring for 30 minutes. Theprecipitated solid was collected by filtration, and further washed withwater (180 ml) twice and hexane once. The resulting solid was driedunder reduced pressure to give5-hydroxymethyl-2-mercapto-1-propylimidazole (71.2 g) as colorlesscrystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.87 (3H, t, J=7.4 Hz), 1.61-1.79 (2H, m),3.91 (2H, t, J=7.4 Hz), 4.32 (2H, s), 5.26 (1H, br), 6.79 (1H, s), 11.95(1H, s).

Elementary analysis C₇H₁₂N₂OS.0.25H₂O, Calcd. C, 47.57; H, 7.13; N,15.85. Found. C, 47.22; H, 6.94; N, 15.99.

REFERENCE EXAMPLE 171

To 5.0 M nitric acid (370 ml) was added sodium nitrite (1.14 g), andthen 5-hydroxymethyl-2-mercapto-1-propylimidazole (71.0 g) was added at0° C. portionwise. The mixture was returned to room temperature andstirred for 2 hours, followed by adding water (200 ml). Thereto wasadded potassium carbonate at 0° C. to neutralize the mixture. Then, thesolvent was distilled off under reduced pressure. Ethanol was addedthereto, insolubles were filtered off, and the solvent was thendistilled off under reduced pressure. To the resulting residue was addedmethanol-ethyl acetate, and then basic silica gel was added thereto. Theresulting mixture was purified by basic silica gel column chromatography(methanol-ethyl acetate=1:8). The resulting solid was recrystallizedfrom diisopropyl ether-ethyl acetate to give5-hydroxymethyl-1-propylimidazole (33.6 g) as brown crystals.

¹H-NMR (200 MHz, CDCl₃) δ 0.96 (3H, t, J=7.4 Hz), 1.76-1.94 (2H, m),3.97 (2H, t, J=7.2 Hz), 4.63 (2H, s), 6.97 (1H, s), 7.48 (1H, s).

REFERENCE EXAMPLE 172

To 5-hydroxymethyl-1-propylimidazole (33.0 g) was added thionyl chloride(80 ml) at 0° C. portionwise, and the mixture was heated at 90° C. for30 minutes under a nitrogen atmosphere. The mixture was returned to roomtemperature, and then the solvent was distilled off under reducedpressure. The resulting residue was dissolved in methanol, and thesolvent was again distilled off under reduced pressure. The resultingsolid was recrystallized from ethyl acetate to give5-chloromethyl-1-propylimidazole hydrochloride (43.8 g) as colorlesscrystals.

¹H-NMR (200 MHz, DMSO-d₆) δ 0.92 (3H, t, J=7.4 Hz), 1.84-1.95 (2H, m),4.18 (2H, t, J=7.2 Hz), 5.04 (2H, s), 7.82 (1H, s), 9.24 (1H, s).

REFERENCE EXAMPLE 173

4-Aminothiophenol (2.5 g) was dissolved in water (2.5 ml) andisopropanol (10 ml). Triethylamine (5.5 ml) was added thereto, and thenthe mixture was cooled to −15 to −10° C. A solution of5-(chloromethyl)-1-propyl-1H-imidazole hydrochloride (3.9 g) in water(2.5 ml) was added dropwise thereto at −15 to −10° C., and the mixturewas stirred at the same temperature for 1 hour. After isopropanol wasdistilled off under reduced pressure, methyl isobutyl ketone (25 ml) wasthen added thereto, and the organic layer was washed with water. To theorganic layer was added activated carbon (0.1 g), and the mixture wasstirred at room temperature for 10 minutes. The organic layer wasconcentrated and dissolved in methyl isobutyl ketone (30 ml).Separately, di-p-toluoyl-(D)-tartaric acid (7.7 g) was dissolved in amixed solution of toluene (90 ml) and methyl isobutyl ketone (60 ml),and to the solution was added water (3.6 ml). Then, the above methylisobutyl ketone solution was slowly added dropwise thereto over 2 hours.After stirring the resulting mixture for 1 hour, aqueous 30% hydrogenperoxide (6.8 g) was added thereto, and the mixture was stirred at roomtemperature for 24 hours. Methanol (30 ml) was added thereto, and themixture was stirred at 50° C. for 8 hours. Water (30 ml) was addedthereto, and the mixture was stirred at room temperature for 5 hours.The precipitated crystals were collected by filtration and washed withwater (30 ml) to give(−)-4-{[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl}phenylaminedi-p-toluoyl-D-tartrate monohydrate (7.1 g).

m.p. 134-136° C.

REFERENCE EXAMPLE 174

A suspension of 5-bromo-2-fluorobenzaldehyde (300 mg), ethylpyrrolidin-3-yl acetate hydrochloride (401 mg) and sodium carbonate (330mg) in DMSO (10 ml) and water (5 ml) was stirred for 4 hours at 90° C.under a nitrogen atmosphere. After returning to room temperature, waterwas added thereto and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated brine, and dried overmagnesium sulfate. The solvent was distilled off under reduced pressure,and then the resulting residue was separated and purified by silica gelcolumn chromatography (hexane:ethyl acetate=10:1→hexane:ethylacetate=3:1) to give5-bromo-2-[3-(2-ethoxy-2-oxoethyl)pyrrolidin-1-yl]benzaldehyde (455 mg)as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 1.27 (3H, t, J=6.9 Hz), 1.69-1.79 (1H, m),2.15-2.30 (1H, m), 2.46-2.49 (2H, m), 2.65-2.80 (1H, m), 3.15-3.21 (1H,m), 3.30-3.60 (3H, m), 4.12-4.19 (2H, m), 6.71 (1H, d, J=9.0 Hz), 7.43(1H, dd, J=9.0, 2.4 Hz), 7.79 (1H, d, J=2.4 Hz), 9.99 (1H, s).

REFERENCE EXAMPLE 175

A solution of5-bromo-2-[3-(2-ethoxy-2-oxoethyl)pyrrolidin-1-yl]benzaldehyde (4.3 g)and tert-butyl 2-(triphenylphosphoranylidene)propanoate (7.4 g) intoluene (200 ml) was refluxed for 8 hours under a nitrogen atmosphere.After returning to room temperature, water was added thereto and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over magnesium sulfate. After distillingoff the solvent under reduced pressure, the resulting residue waspurified by silica gel column chromatography (hexane:ethylacetate=9:1→hexane:ethyl acetate=7:3) to give tert-butyl(2E)-3-[5-bromo-2-[3-(2-ethoxy-2-oxoethyl)pyrrolidin-1-yl]phenyl]-2-methylacrylate(2.64 g) as a brown oily material.

¹H-NMR (300 MHz, CDCl₃) δ 1.26 (3H, t, J=7.2 Hz), 1.53-1.65 (10H, m),1.94 (3H, d, J=1.5 Hz), 2.10-2.20 (1H, m), 2.43-2.46 (2H, m), 2.55-2.70(1H, m), 2.93-2.96 (1H, m), 3.20-3.36 (3H, m), 4.11-4.18 (2H, m), 6.65(1H, d, J=8.4 Hz), 7.20-7.28 (2H, m), 7.54 (1H, s).

REFERENCE EXAMPLE 176

A suspension of tert-butyl(2E)-3-[5-bromo-2-[3-(2-ethoxy-2-oxoethyl)pyrrolidin-1-yl]phenyl]-2-methylacrylate(2.5 g), 4-(2-butoxyethoxy)phenylboric acid (1.71 g) and potassiumcarbonate (1.99 g) in toluene (50 ml), ethanol (5 ml) and water (5 ml)was stirred for 1 hour under an argon atmosphere. Then,tetrakis(triphenylphosphine)palladium (324 mg) was added thereto, andthe resulting mixture was refluxed for 5 hours. After returning to roomtemperature, water was added thereto and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over magnesium sulfate. The solvent was distilled off underreduced pressure, and then the resulting residue was purified by silicagel column chromatography (hexane:ethyl acetate=18:1→hexane:ethylacetate=4:1) to give tert-butyl(2E)-3-[4′-(2-butoxyethoxy)-4-[3-(2-ethoxy-2-oxoethyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methylacrylate(1.87 g) as a yellow oily material.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2 Hz), 1.27 (3H, t, J=6.3Hz), 1.33-1.70 (14H, m), 2.01 (3H, d, J=1.2 Hz), 2.10-2.20 (1H, m),2.46-2.48 (2H, m), 2.60-2.75 (1H, m), 3.00-3.06 (1H, m), 3.20-3.45 (3H,m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=4.5 Hz), 4.11-4.19 (4H, m),6.84 (1H, d, J=8.4 Hz), 6.96 (2H, d, J=8.7 Hz), 7.33-7.46 (4H, m), 7.69(1H, s).

REFERENCE EXAMPLE 177

tert-Butyl(2E)-3-[4′-(2-butoxyethoxy)-4-[3-(2-ethoxy-2-oxoethyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methylacrylate(1.8 g) was dissolved in ethyl acetate (20 ml). Then, a 4 N hydrochloricacid-ethyl acetate solution (23.9 ml) was added thereto, and the mixturewas stirred for 1 day under a nitrogen atmosphere. Water was addedthereto at 0° C., and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over magnesiumsulfate. After distilling off the solvent under reduced pressure, theresulting solids were washed with hexane to give(2E)-3-[4′-(2-butoxyethoxy)-4-[3-(2-ethoxy-2-oxoethyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methylacrylicacid (1.42 g) as yellow crystals.

m.p. 115.5-116.5° C.

¹H-NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.5 Hz), 1.27 (3H, t, J=7.2Hz), 1.33-1.80 (5H, m), 2.08 (3H, d, J=1.2 Hz), 2.10-2.21 (1H, m),2.46-2.49 (2H, m), 2.65-2.80 (1H, m), 3.02-3.07 (1H, m), 3.20-3.45 (3H,m), 3.55 (2H, t, J=6.6 Hz), 3.80 (2H, t, J=5.1 Hz), 4.12-4.19 (4H, m),6.87 (1H, d, J=8.4 Hz), 6.98 (2H, d, J=8.7 Hz), 7.36-7.47 (4H, m), 7.94(1H, s).

Elementary analysis C₃₀H₃₉NO₆, Calcd. C, 70.70; H, 7.71; N, 2.75. FoundC, 70.33; H, 7.67; N, 2.71.

EXPERIMENTAL EXAMPLE

(1) Cloning of Human CCR5 Chemokine Receptor

Cloning of a CCR5 gene was conducted from human spleen cDNA by a PCRmethod. Using 0.5 ng of spleen cDNA (Toyobo Co., Ltd., QUICK-Clone cDNA)as a template, the PCR reaction was carried out in a DNA Thermal Cycler480 (Perkin Elmer) using a TaKaRa EX Taq (Takara Shuzo Co., Ltd.)(reaction conditions: 30 cycles of treatments at 95° C. for 1 minute, at60° C. for 1 minute, and at 75° C. for 5 minutes) by adding 25 pmol ofprimers, SEQ ID NO. 1 (sequence length: 34; sequence type: nucleic acid;number of chains: a single chain; topology: linear; sequence kind: othernucleic acid, synthetic DNA) described in Experimental Example (1) of WO99/32100, and SEQ ID NO. 2 (sequence length: 34; sequence type: nucleicacid; number of chains: a single chain; topology: linear; sequence kind:other nucleic acid, synthetic DNA) described in Experimental Example (1)of WO 99/32100, respectively, which were prepared by referring to thebase sequence of the CCR5 gene described by Samson et al. (Biochemistry35 (11), 3362-3367 (1996)). The PCR products were subjected to agarosegel electrophoresis to collect DNA fragments of about 1.0 kb. Then, theCCR5 gene was cloned using an Original TA Cloning Kit (Funakoshi Co.,Ltd.).

(2) Preparation of Plasmid for Expression of Human CCR5

The plasmids obtained above were digested with restriction enzymes XbaI(Takara Shuzo Co., Ltd.) and BamHI (Takara Shuzo Co., Ltd.), andsubjected to agarose gel electrophoresis to collect DNA fragments ofabout 1.0 kb. The DNA fragments and a plasmid pcDNA3.1 (Funakoshi Co.,Ltd.) for expression in animal cells, which was previously digested withXbaI and BamHI, were mixed and ligated by DNA Ligation Kit Ver.2 (TakaraShuzo Co., Ltd.). Transformation of E. coli JM109 competent cells(Takara Shuzo Co., Ltd.) gave plasmid pCKR5.

(3) Introduction of the Plasmid for Expression of Human CCR5 into CHO-K1Cells and Expression Thereof

CHO-K1 cells grown in a 750 ml tissue culture flask (Becton Dickinson)using Ham's F12 medium (Nihon Pharmaceutical Co., Ltd.) containing 10%fetal bovine serum (Lifetech Oriental) were collected from the flask byusing 0.5 g/L trypsin-0.2 g/L EDTA (Lifetech Oriental). The cells werethen washed with PBS (Lifetech Oriental), centrifuged (1000 rpm, 5minutes), and suspended in PBS. Next, DNA was introduced into the cellsusing Gene Pulser (Bio-Rad Laboratories Inc.) under the followingconditions. Namely, 8×10⁶ cells and 10 μg of plasmid pCKR5 forexpression of human CCR5 were added into a cuvette of a 0.4 cm-gap, andelectroporation was carried out at an electric voltage of 0.25 kV and acapacitance of 960 μF. Subsequently, the cells were transferred intoHam's F12 medium containing 10% fetal bovine serum, and incubated for 24hours. The cells were again collected, centrifuged, and then suspendedin Ham's F12 medium containing 10% fetal bovine serum and Geneticin(Lifetech Oriental) at a concentration of 500 μg/ml. The suspension ofcells was diluted to a concentration of 10⁴ cells/ml, and inoculated ona 96-well plate (Becton Dickinson) to give Geneticin-resistant strains.

Subsequently, the Geneticin-resistant strains were cultured in the96-well plate (Becton Dickinson), and then CCR5-expressing cells wereselected from the resistant strains. Namely, an assay buffer (Ham's F12medium containing 0.5% BSA, and 20 mM HEPES (Wako Pure ChemicalIndustries, Ltd., pH 7.2)) containing 200 pM [¹²⁵I]-RANTES (Amersham) asa ligand was added to each well and the binding reaction was carried outat room temperature for 40 minutes. Each well plate containing the cellswas washed with ice-cooled PBS, and then to each well was added 1 M NaOHin an amount of 50 μl/well, which was stirred. The cells to which theligand bound specifically, i.e., CCR5/CHO strains, were selected bymeasurement of radioactivity by γ-counter.

(4) Evaluation of Compound Based on CCR5 Antagonist Activity

The CCR5/CHO strains were inoculated on a 96-well microplate at aconcentration of 5×10⁴ cells/well, respectively and were cultured for 24hours. After the medium was removed by suction, to each well was addedan assay buffer containing a test compound (1 μM), and [¹²⁵I]-RANTES(Amersham) used as a ligand at a concentration of 100 pM. The reactionwas carried out at room temperature for 40 minutes. After the assaybuffer was removed by suction, each well plate containing the cells werewashed with ice-cooled PBS twice. Then, to each well was added 200 μl ofMicroScint-20 (Packard Industry Company, Inc.), and the radioactivitywas measured with TopCount (Packard Industry Company, Inc.).

According to the method above, inhibitory ratios to CCR5 binding of thetest compounds were determined. The results are shown in Table 1. TABLE1 Compound No. Binding Inhibitory Ratio (%) 17 100 23 100 26 90 29 10035 100 38 93 39 99 40 100 41 100 42 100 43 86 47 96 48 98 49 100 50 10057 100 58 95 59 89 60 91 61 94 62 100

FORMULATION EXAMPLE 1 (Capsules)

(1) (Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3- 40 mgcarboxypyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazole-5-yl)methyl]sulfinyl]phenyl]acrylamide (2) lactose 61 mg (3)microcrystalline cellulose 18 mg (4) magnesium stearate 1 mg contents of1 capsule 120 mg

After mixing (1), (2), (3) and (4), the mixture is filled in gelatincapsules.

FORMULATION EXAMPLE 2 (Capsules)

(1) (Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3- 40 mgmethylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazole-5-yl)methyl]sulfinyl]phenyl]acrylamide (2) lactose 61 mg (3)microcrystalline cellulose 18 mg (4) magnesium stearate 1 mg contents of1 capsule 120 mg

After mixing (1), (2), (3) and (4), the mixture is filled in gelatincapsules.

FORMULATION EXAMPLE 3 (Capsules)

(1) (S)-(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]- 40 mg2-pyrrolidin-1-ylpyridin-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazole-5-yl)methyl]sulfinyl] phenyl]acrylamide (2)lactose 61 mg (3) microcrystalline cellulose 18 mg (4) magnesiumstearate 1 mg contents of 1 capsule 120 mg

After mixing (1), (2), (3) and (4), the mixture is filled in gelatincapsules.

FORMULATION EXAMPLE 4 (Tablets)

(1) (Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3- 40 mgmethylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazole-5-yl)methyl]sulfinyl]phenyl]acrylamide (2) mannitol 51.2 mg (3)microcrystalline cellulose 18 mg (4) hydroxypropyl cellulose 3.6 mg (5)croscarmellose sodium 6 mg (6) magnesium stearate 1.2 mg 1 tablet 120 mg

(1), (2), (3) and (4) are mixed and granulated. To the granules areadded (5) and (6), and the mixture is compressed into tablets.

FORMULATION EXAMPLE 5 (Tablets)

(1) (Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3- 40 mgcarboxypyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazole-5-yl)methyl]sulfinyl]phenyl]acrylamide (2) mannitol 51.2 mg (3)microcrystalline cellulose 18 mg (4) hydroxypropyl cellulose 3.6 mg (5)croscarmellose sodium 6 mg (6) magnesium stearate 1.2 mg 1 tablet 120 mg

(1), (2), (3) and (4) are mixed and granulated. To the granules areadded (5) and (6), and the mixture is compressed into tablets.

FORMULATION EXAMPLE 6 (Tablets)

(1) (S)-(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]- 40 mg2-pyrrolidin-1-ylpyridin-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazole-5-yl)methyl] sulfinyl]phenyl]acrylamide (2)mannitol 51.2 mg (3) microcrystalline cellulose 18 mg (4) hydroxypropylcellulose 3.6 mg (5) croscarmellose sodium 6 mg (6) magnesium stearate1.2 mg 1 tablet 120 mg

(1), (2), (3) and (4) are mixed and granulated. To the granules areadded (5) and (6), and the mixture is compressed into tablets.

INDUSTRIAL APPLICABILITY

The compound represented by formula (I) of the present invention or asalt thereof has strong CCR5 antagonistic activity and improved watersolubility, and thus can be used advantageously in prevention andtreatment of a variety of HIV infection, for example, AIDS, in humans.

1. A compound represented by the formula:

wherein R¹ is a 5- or 6-membered ring which may be substituted; R³ is ahydrogen atom, a lower alkyl group which may be substituted or a loweralkoxy group which may be substituted; R⁷ and R⁸ are each a hydrogenatom or a lower alkyl group which may be substituted; Z¹ is a 5- or6-membered aromatic ring which may be further substituted; Z² is a grouprepresented by -Z^(2a)-W¹-Z^(2b)-, wherein Z^(2a) and Z^(2b) are each O,S(O)_(m) (wherein m is 0, 1 or 2), an imino group which may besubstituted, or a bond, and W¹ is an alkylene chain which may besubstituted, an alkenylene chain which may be substituted, or a bond; Xis N or CR, wherein R represents a hydrogen atom, a lower alkyl groupwhich may be substituted, a lower alkoxy group which may be substitutedor an acyl group which may be substituted, or R and the adjacent R⁴ mayform a 5- or 6-membered alicyclic heterocyclic group; R⁴ is NR⁵R⁶,wherein R⁵ and R⁶ each represent a hydrogen atom, a hydrocarbon groupwhich may be substituted, a heterocyclic group which may be substitutedor an acyl group which may be substituted, or R⁵ and R⁶ are bonded toeach other to form a heterocyclic group which may be substitutedrepresented by NR⁵R⁶; and R² is (1) an amino group which may besubstituted, in which the nitrogen atom may be converted to a quaternaryammonium or an oxide, (2) a nitrogen-containing heterocyclic group whichmay be substituted and may contain a sulfur atom or an oxygen atom asthe ring-constituting atom, in which the nitrogen atom may be convertedto a quaternary ammonium or an oxide, (3) a group represented by theformula:

wherein k represents 0 or 1, and when k is 0, the phosphorus atom mayform a phosphonium salt; R⁹ and R¹⁰ are each a hydrocarbon group whichmay be substituted, a hydroxy group which may be substituted or an aminogroup which may be substituted; or R⁹ and R¹⁰ may be bonded to eachother to form a cyclic group with the adjacent phosphorus atom, (4) anamidino group which may be substituted, or (5) a guanidino group whichmay be substituted; or a salt thereof.
 2. A prodrug of the compoundaccording to claim
 1. 3. The compound according to claim 1, wherein R¹is a benzene, a furan, a thiophene, a pyridine, a cyclopentane, acyclohexane, a pyrrolidine, a piperidine, a piperazine, a morpholine, athiomorpholine or a tetrahydropyran, each of which may be substituted.4. The compound according to claim 1, wherein R¹ is a benzene which maybe substituted.
 5. The compound according to claim 1, wherein NR⁵R⁶ is aheterocyclic group which may be substituted.
 6. The compound accordingto claim 1, wherein Z¹ is a benzene which may be substituted with asubstituent selected from (1) a halogen atom, (2) a C₁₋₄ alkyl groupwhich may be substituted with a halogen atom, and (3) a C₁₋₄ alkoxygroup which may be substituted with a halogen atom.
 7. The compoundaccording to claim 1, wherein Z¹ is a benzene which may be substitutedwith a methyl group or a trifluoromethyl group.
 8. The compoundaccording to claim 1, wherein Z² is a group represented byZ^(2a)-W²-Z^(2b)-, wherein Z^(2a) and Z^(2b) are each O, S(O)_(m)(wherein m is 0, 1 or 2), an imino group which may be substituted, or abond, and W² is an alkylene chain which may be substituted.
 9. Thecompound according to claim 1, wherein Z² is a group represented by—CH₂—, —CH(OH)— or —S(O)_(m)—CH₂— (wherein m is 0, 1 or 2).
 10. Thecompound according to claim 1, wherein Z² is a group represented by—S(O)—CH₂— (wherein m is 0, 1 or 2).
 11. The compound according to claim1, wherein R² is (1) an amino group which may be substituted, in whichthe nitrogen atom may be converted to a quaternary ammonium or an oxide,(2) a nitrogen-containing heterocyclic group which may be substitutedand may contain a sulfur atom or an oxygen atom as the ring-constitutingatom, in which the nitrogen atom may be converted to a quaternaryammonium or an oxide, (3) an amidino group which may be substituted, or(4) a guanidino group which may be substituted.
 12. The compoundaccording to claim 1, wherein R² is an amino group which may besubstituted, or a nitrogen-containing heterocyclic group which may besubstituted and may contain a sulfur atom or an oxygen atom as thering-constituting atom.
 13. The compound according to claim 1, whereinR² is —NRR′, wherein R and R′ are each an aliphatic hydrocarbon groupwhich may be substituted or an alicyclic heterocyclic group which may besubstituted.
 14. The compound according to claim 1, wherein R² is anitrogen-containing aromatic heterocyclic group which may besubstituted.
 15. The compound according to claim 1, wherein R² is animidazolyl group which may be substituted or a triazolyl group which maybe substituted.
 16. The compound according to claim 1, wherein R¹ is abenzene, a furan, a thiophene, a pyridine, a cyclopentane, acyclohexane, a pyrrolidine, a piperidine, a piperazine, a morpholine, athiomorpholine or a tetrahydropyran, each of which may be substitutedwith a halogen, a nitro, a cyano, a C₁₋₆ alkyl, a C₁₋₆ alkoxy, a C₁₋₆alkoxy-C₁₋₆ alkyl or a C₁₋₆ alkoxy-C₁₋₆ alkoxy; Z¹ is benzene which maybe substituted with a substituent selected from (1) a halogen atom, (2)a C₁₋₄ alkyl group which may be substituted with a halogen atom, and (3)a C₁₋₄ alkoxy group which may be substituted with a halogen atom; Z² is-Z^(2a)-W¹-Z^(2b)-, wherein Z^(2a) and Z^(2b) are each O, S(O)_(m)(wherein m is 0, 1 or 2), an imino group which may be substituted with aC₁₋₄ alkyl group, or a bond, and W¹ is a bond, or a C₁₋₄ alkylene chainor a C₂₋₄ alkenylene chain, each of which may be substituted with a C₁₋₆alkyl, a hydroxy group, a hydroxyimino or a C₁₋₆ alkoxyimino; and R² isan amino group which may be substituted with a C₁₋₄ alkyl group, or anitrogen-containing heterocyclic group which may contain a sulfur atomor an oxygen atom as the ring-constituting atom and may be substitutedwith a C₁₋₄ alkyl group.
 17. A compound represented by the formula:

wherein R^(1a) is a (C₁₋₆ alkoxy-C₁₋₆ alkoxy)phenyl; R^(2a) is (1) anN-C₁₋₆ alkyl-N-tetrahydropyranylamino, (2) an imidazolyl which may besubstituted with C₁₋₆ alkyl which may be substituted, or (3) a triazolylwhich may be substituted with a C₁₋₆ alkyl which may be substituted; R³is a hydrogen atom, a lower alkyl group which may be substituted or alower alkoxy group which may be substituted; R^(4a) is NR^(5a)R^(6a),wherein R^(5a) and R^(6a) are bonded to each other to form aheterocyclic group which may be substituted represented byNR^(5a)R^(6a); X^(a) is CH or N; na is 0 or 1; and Z^(2a) is a bond, S,SO or SO₂; or a salt thereof.
 18. The compound according to claim 17,wherein Z^(2a) is SO.
 19. The compound according to claim 18, whereinZ^(2a) is SO having a configuration of (S).
 20. The compound accordingto claim 17, wherein R^(4a) is a 1-pyrrolidinyl group which may besubstituted. 21.(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-methylpyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide,(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-[3-(hydroxymethyl)pyrrolidin-1-yl]-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamide,(Ss)-(2E)-3-[4′-(2-butoxyethoxy)-4-(3-carboxypyrrolidin-1-yl)-1,1′-biphenyl-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol)-5-yl]methyl]sulfinyl]phenyl]acrylamideand diastereomers thereof. 22.(Ss)-(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-[3-(hydroxymethyl)pyrrolidin-1-yl]pyridin-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidazol-5-yl)methyl]sulfinyl]phenyl]acrylamideand a diastereomer thereof, and(S)-(2E)-3-[5-[4-(2-butoxyethoxy)phenyl]-2-pyrrolidin-1-ylpyridin-3-yl]-2-methyl-N-[4-[[(1-propyl-1H-imidzol-5-yl)methyl]sulfinyl]phenyl]acrylamide.23. A process for producing a compound represented by the formula:

wherein R^(2″) is (1) an amino group which may be substituted, in whichthe nitrogen atom may be converted to a quaternary ammonium, (2) anitrogen-containing heterocyclic group which may be substituted and maycontain a sulfur atom or an oxygen atom as the ring-constituting atom,in which the nitrogen atom may be converted to a quaternary ammonium, or(3) a group represented by formula:

wherein k represents 0 or 1, and when k is 0, the phosphorus atom mayform a phosphonium salt; R⁹ and R¹⁰ are each a hydrocarbon group whichmay be substituted, a hydroxy group which may be substituted or an aminogroup which may be substituted; or R⁵ and R⁶ may be bonded to each otherto form a cyclic group with the adjacent phosphorus atom; and the othersymbols have the same meanings as defined in claim 1; or a salt thereof,which comprises subjecting a compound represented by the formula:

wherein each symbol has the same meaning as defined in claim 1; or asalt thereof or a reactive derivative thereof, and a compoundrepresented by the formula:

wherein Z¹ and Z² have the same meaning as defined in claim 1, andR^(2″) has the same meaning as defined above; or a salt thereof to acondensation reaction, and then optionally to deprotection,oxidation-reduction and/or quaternization reaction.
 24. A pharmaceuticalcomposition comprising the compound represented by the formula:

wherein R¹ is a 5- or 6-membered ring which may be substituted; R³ is ahydrogen atom, a lower alkyl group which may be substituted or a loweralkoxy group which may be substituted; R⁷ and R⁸ are each a hydrogenatom or a lower alkyl group which may be substituted; Z¹ is a 5- or6-membered aromatic ring which may be further substituted; Z² is a grouprepresented by -Z^(2a)-W¹-Z^(2b)-, wherein Z^(2a) and Z^(2b) are each O,S(O)_(m) (wherein m is 0, 1 or 2), an imino group which may besubstituted, or a bond, and W¹ is an alkylene chain which may besubstituted, an alkenylene chain which may be substituted, or a bond; Xis N or CR, wherein R represents a hydrogen atom, a lower alkyl groupwhich may be substituted, a lower alkoxy group which may be substitutedor an acyl group which may be substituted, or R and the adjacent R⁴ mayform a 5- or 6-membered alicyclic heterocyclic group; R⁴ is NR⁵R⁶,wherein R⁵ and R⁶ each represent a hydrogen atom, a hydrocarbon groupwhich may be substituted, a heterocyclic group which may be substitutedor an acyl group which may be substituted, or R⁵ and R⁶ are bonded toeach other to form a heterocyclic group which may be substitutedrepresented by NR⁵R⁶; and R² is (1) an amino group which may besubstituted, in which the nitrogen atom may be converted to a quaternaryammonium or an oxide, (2) a nitrogen-containing heterocyclic group whichmay be substituted and may contain a sulfur atom or an oxygen atom asthe ring-constituting atom, in which the nitrogen atom may be convertedto a quaternary ammonium or an oxide, (3) a group represented by theformula:

wherein k represents 0 or 1, and when k is 0, the phosphorus atom mayform a phosphonium salt; R⁹ and R¹⁰ are each a hydrocarbon group whichmay be substituted, a hydroxy group which may be substituted or an aminogroup which may be substituted; or R⁹ and R¹⁰ may be bonded to eachother to form a cyclic group with the adjacent phosphorus atom, (4) anamidino group which may be substituted, or (5) a guanidino group whichmay be substituted; or a salt thereof or a prodrug thereof.
 25. Thepharmaceutical composition according to claim 24, which is a CCRantagonist.
 26. The pharmaceutical composition according to claim 25,wherein CCR is CCR5 and/or CCR2.
 27. The pharmaceutical compositionaccording to claim 25, wherein CCR is CCR5.
 28. The pharmaceuticalcomposition according to claim 24, which is a prophylactic and/ortherapeutic agent for HIV infection, chronic rheumatoid arthritis,autoimmune diseases, allergic diseases, ischemic brain cell disorder,cardiac infarction, nephritis/nephropathy, arteriosclerosis orgraft-versus-host diseases.
 29. The pharmaceutical composition accordingto claim 24, which is a prophylactic and/or therapeutic agent for HIVinfection.
 30. The pharmaceutical composition according to claim 24,which is a prophylactic and/or therapeutic agent for AIDS.
 31. Thepharmaceutical composition according to claim 24, which is a suppressiveagent for disease progression of AIDS.
 32. A method for preventing ortreating HIV infection, chronic rheumatoid arthritis, autoimmunediseases, allergic diseases, ischemic brain cell disorder, cardiacinfarction, nephritis/nephropathy, arteriosclerosis or graft-versus-hostdiseases, which comprises administering an effective amount of thecompound according to claim 1, a salt or prodrug thereof to a subject inneed thereof.
 33. Use of the compound according to claim 1, a salt orprodrug thereof, for the manufacture of a prophylactic and/ortherapeutic agent for HIV infection, chronic rheumatoid arthritis,autoimmune diseases, allergic diseases, ischemic brain cell disorder,cardiac infarction, nephritis/nephropathy, arteriosclerosis orgraft-versus-host diseases.